Abstract
Various new treatments are emerging constantly in anti-tumor therapies, including chemotherapy, immunotherapy, and targeted therapy. However, the efficacy is still not satisfactory. Astragalus polysaccharide is an important bioactive component derived from the dry root of Radix astragali. Studies found that astragalus polysaccharides have gained great significance in increasing the sensitivity of anti-tumor treatment, reducing the side effects of anti-tumor treatment, reversing the drug resistance of anti-tumor drugs, etc. In this review, we focused on the role of astragalus polysaccharides in tumor immune microenvironment. We reviewed the immunomodulatory effect of astragalus polysaccharides on macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes. We found that astragalus polysaccharides can promote the activities of macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes and induce the expression of a variety of cytokines and chemokines. Furthermore, we summarized the clinical applications of astragalus polysaccharides in patients with digestive tract tumors. We summarized the effective mechanism of astragalus polysaccharides on digestive tract tumors, including apoptosis induction, proliferation inhibition, immunoactivity regulation, enhancement of the anticancer effect and chemosensitivity. Therefore, in view of the multiple functions of astragalus polysaccharides in tumor immune microenvironment and its clinical efficacy, the combination of astragalus polysaccharides with antitumor therapy such as immunotherapy may provide new sparks to the bottleneck of current treatment methods.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
1 Introduction
As one of traditional Chinese herbal medicine, Radix astragali has a long history of use in medicine. Many studies have discovered that radix astragali has a wide range of biological activities, such as anti-aging, anti-tumor, antioxidant, immunomodulation, and anti-inflammation. Thus, it is widely used in the treatment of cardiovascular diseases, diabetes mellitus, cancers, and other diseases [1,2,3,4]. Thereinto, radix astragali has complex chemical ingredients, the major components of which are polysaccharides (APS), flavonoids, and astragaloside IV(AS-IV) [2, 5, 6]. Amongst them, astragalus polysaccharides are the vital natural active component derived from radix astragali, the immunomodulatory nature of which is the most significant [7,8,9]. A large number of in vitro and in vivo studies have confirmed that astragalus polysaccharides can regulate the immune system. According to research, APS is an excellent immunopotentiator of both humoral and cellular immunity [10]. APS accelerates the maturation of DCs, improves their capacity for antigen presentation, and decreases their endocytic activity. Additionally, DCs could differentiate as a result of APS, which would then activate T cells [11]. APS is able to control T cell immunity. Through binding to anti-Toll-like receptor 4 (TLR4) on Tregs, APS might limit CD4+CD25+ Treg activity and cause the transition from T helper 2 cell (Th2) to T helper 1 cell (Th1) by engaging CD4+ T cells [12, 13]. Also, APS can activate B cells through membrane Ig in a way that is independent of TLR4 [14].
The tumor immune microenvironment (TIME) refers to the environment created by immune cells and their products in tumor tissues. It has been shown that TIME is directly associated to the development, growth, and spread of tumors as well as to the clinical prognosis of tumor patients [15, 16]. At present, there are more and more studies on the tumor immune microenvironment in clinic. For example, the study in gastric adenocarcinoma found that by modifying the innate as well as adaptive immune responses, we can influence the development of epithelial-derived gastric adenocarcinoma (GAC) by generating the immunosuppressive surroundings [17]. In addition, we also noticed that bidirectional interactions between gastric cancer stem cells (GCSCs) and immune cells in gastric cancer, about how cancer stem cells induce the reprogramming of leukocytes. And this could lead to immune cells that are pro-tumorigenic, orchestrating metastasis, chemoresistance, tumorigenicity, and even a rise in cancer cells with stem-like features. This might inspire fresh thought for immunotherapy targeting GCSC-related markers [18,19,20]. At present, immunotherapy has significantly outperformed traditional chemotherapy and radiotherapy in the treatment of cancers. Nevertheless, the immunosuppressive characteristics in tumor microenvironment (TME) cause difficulties in clinical efficacy and have severe side effects. Stimulating the TIME may be a critical step in improving the efficacy of current immunotherapies. According to the growing evidence, the effectiveness of immunotherapy can be multiplied by affecting the tumor immunosuppressive microenvironment [21,22,23,24,25]. Therefore, in-depth understanding the role of astragalus polysaccharides and tumor immune microenvironment is necessary to develop and optimize novel and effective cancer immunotherapies.
Digestive tract tumors are one of the most common malignant tumors globally, which have a high incidence and mortality rate [26]. The current treatment options of these tumors roughly include surgery, chemotherapy and radiotherapy, which are the first line treatments for advanced tumors that only prolong the survival of patients. However, tumors quickly develop strong resistance to chemotherapy medicines, while there is a high rate of recurrence and metastasis, and patients have a poor prognosis overall and serious adverse reactions [27]. Currently, immunotherapy may be one of the effective therapies to overcome the difficulties [28]. APS, a water-soluble heteropolysaccharide, stimulates and controls the immune system. The anticancer effect of APS may be enhanced by the promotion of the activities of macrophages, natural killer cells, dendritic cells, T lymphocytes, and B lymphocytes as well as the induction of a number of cytokines and chemokines [7, 29, 30]. With a focus on the application in the immunotherapy of digestive tract tumors, this review presents the research advances of APS in TIME.
2 Regulation effect of APS on immunity
2.1 Tumor-associated macrophages
Macrophages are main cells in the innate immune system, as well as the capital component of the mononuclear phagocyte system (MPS) [31]. Macrophages that appear in the TME are defined as tumor-associated macrophages (TAMs), which are widely present in various tumors [32]. While TAMs are the most infiltrated immune cells in the TME, they have been thoroughly investigated for their pro-tumoral actions, including tumor initiation, angiogenesis, metastasis, drug resistance, and antitumor immunosuppression [33,34,35,36,37]. It has been suggested that functional diversity of macrophages is relevant to their plasticity, and that molecules in TIME may adjust their functional phenotypes. Depending on the activation state, TAMs have a dual role on cancer with classically activated (M1) and alternatively activated (M2) cells commonly acting antitumor and protumor functions [38, 39]. M1 type macrophages have anti-tumor effects. Based on studies, M1 macrophages can destroy and clear tumor cells, which is consistent with their natural function to remove foreign objects. By activating pro-immunostimulating leukocytes and swallowing tumor cells, the M1 macrophages stimulate the cytokine production in the TME and promote tumor cell destruction [32]. M2 macrophages can promote tumor cell proliferation and invasion. There are studies found that M2 macrophages may contribute to basement membrane breakdown, deposition, angiogenesis, leukocyte recruitment, and overall immune suppression, and all of them could accelerate tumor development in both primary and metastatic sections [40,41,42]. Based on studies, M2 phenotype, which presents immunosuppression and promotes tumor growth, is dominant in TAMs. Therefore, the potential anticancer immunotherapy concentrates on M2 phenotype by eliminating them in the TME or converting M2 phenotype into M1 phenotype, which increases their cytotoxicity directly and indirectly prompts cytotoxic T cells to kill tumor cells [42,43,44,45,46]. Relevant studies have suggested that APS induce the polarization of macrophage to M1 phenotype by the Notch signaling pathway, which may enhance tumor killing and suppress tumor growth [47]. An experimental study in lung cancer found that APS can regulate the M1/M2 macrophage pool, facilitate DC maturation and enhance the anticancer effect of traditional chemotherapy drugs [48]. The research on breast cancer cell has demonstrated that APS can trigger the release of NO and tumor necrosis factor (TNF) from macrophages, possibly by activating of the TLR4-mediated MyD88-dependent signaling pathway, which directly blocks tumor growth [49,50,51]. The cell cycle arrest (G2 phase) and cell apoptosis via the mitochondrial apoptosis pathway induced by APS-mediated macrophages was found to dramatically restrict the development of 4T1 cells [52]. An animal experiment has shown that astragalus membranaceus polysaccharides (AMP) (100 and 400 mg/kg) were able to successfully limit the solid tumor growth in BALB/c mice grafted by H22 hepatocarcinoma. Moreover, AMP could increase the secretion of interleukin-2 (IL-2), IL-12 and TNF-α and lowered interleukin-10 (IL-10) level in serum [53]. In conclusion, APS can exert anti-tumor effects through influencing the polarization of TAMs in the immune microenvironment and induce the expression of a variety of cytokines, thus laying the foundation for further exploration of APS as a synergistic agent for immunotherapy.
2.2 Dendritic cells
Tumor-associated antigens (TAAs) need to be transferred to lymphoid organs and delivered to T cells by antigen-presenting cells (APCs) in order to trigger effective immune responses. The primary professional APCs are macrophages, dendritic cells (DCs) and B cells. DCs have special capabilities and are more effective than macrophages and B cells at stimulating T cells for migration [54,55,56]. DCs continuously investigate peripheral tissue with dendrites, capture and process antigens, migrate towards lymphoid organs, and present antigens to T cells, which will directly lead to the T cell activation and polarization [57,58,59,60,61]. Furthermore, the diverse phenotypic and functional heterogeneity of DCs indicate their high plasticity and capacity to modify the acquired immune response based on TIME [62]. DCs have been shown in mouse cancer models to be able to collect tumor antigens secreted by tumor cells, whether they are still alive or have dead, and cross-present these antigens to T lymphocytes in lymph nodes. As a result, tumor specific cytotoxic T lymphocytes (CTLs) are generated, contributing to the tumor rejection [63, 64]. There are studies that have shown DCs in TIME can significantly impact the functions of antitumor T cells [65,66,67,68]. For example, the marginating DCs in TME can cross-present tumor antigens and continuously engage tumor specific T cells [69]. DCs in tumor-associated tertiary lymphoid structures signal Th1 cytotoxic immune environment and advance a protective T-cell-mediated immune response against tumors [70]. DCs could benefit from APS in a synergistic way. According to the research, APS can accelerate the mature of DCs. In order to have a better anticancer effect, APS may increase the expression of the surface molecules CD80 and CD86, accelerate DCs maturation, and activate CTLs [71]. In mice given the HBV-DNA vaccination, APS (500 ug/mouse) as an adjuvant could promote DCs maturation and increase the expression of major histocompatibility complex I (MHC I), major histocompatibility complex II (MHC II), CD40, CD80, and CD86 [10]. By improving the expression of CD40, CD80, CD86, and MHC II as well as promoting the generation of NO, the pure polysaccharide APSII (1.67–45 ug/ml) may also be able to speed up the DCs mature [72]. Astragalus mongholicus polysaccharides (ASP) could increase the expression of CD11c and MHC class II molecules on DC surface and the secretion of IL-12, priming a strong stimulation of T lymphocytes growth and differentiation [11]. ASPC (3 mg/kg) might increase the number of CD80, CD103, and CD86 as well as promote the functional maturation of DCs in non-small cell lung cancer-bearing mice. This would improve the anticancer immune response carried out by T cells [48]. In addition, via improving the expression of MHC II, CD80, and CD86 on the surface of DCs, APS might stimulate the activation of DCs, which could strengthen the interactions between DCs and T cells [73]. In the study, APS can stimulate the differentiation of naturally IL-12 producing DCs, which can activate T lymphocyte immunological activity and transform Th2 to Th1 cells [74]. In summary, APS can strengthen the T cell-mediated antitumor immune responses by activating the differentiation and maturation of DCs. This may provide a new helper for tumor immunotherapy.
2.3 Natural killer cells
The antiviral and anticancer features of natural killer (NK) cells make them significant effector lymphocytes [75, 76]. About 15% lymphocytes in circulation are NK cells, which are primarily found in the peripheral blood but also appear in a variety of organs such as the liver, lung, kidney and bone marrow [77, 78]. NK cells play a significant role in antitumor immunity by direct cytolysis and IFN-γ production as their cytotoxic effect is free of antigen pre-sensitization and there is no MHC restriction [79, 80]. NK cells are also effective in eliminating metastatic cancer cells and cancer stem cells [81,82,83,84]. So far, conventional tumor treatments can induce stress responses in tumor cells, which help NK cells identify them. For example, several chemotherapy drugs can increase the NK cell-activating ligands on tumor cells, thus increasing their sensitivity to NK cell-mediated lysis [85,86,87]. Meanwhile, several researches have showed that APS can influence the activity of NK cells and the expression of immune components like IFN-γ, TNF-α, granzyme-B and perforin, which might strengthen antitumor effect [29]. The mechanisms that APS activates NK cells were further studied. In H22 tumor-bearing mice, researchers found that the impaired signal transduction may lead to low response of NK cells, but APS can change the response state of NK cells in tumor cells. [88]. Experiments in vitro have demonstrated that the water-soluble polysaccharide AMP and its derivatives can use pro-inflammatory mediators and cytokines by NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways to stimulate the NK cells [89]. The intranasal treatment of APS increased the number of CD11c+ DCs in the mesenteric lymph nodes (mLN), which further activated NK cells and T cells. Thus, APS could be applied as an adjuvant to enhance the antitumor effect of immune checkpoint inhibitors [90]. In short, APS can affect antitumor efficacy of the drugs through regulating the activity of NK cells and increasing the expression of immune factors.
2.4 T and B lymphocytes
It takes a longer time period for adaptive immune system to activate, which is related to activation of T and B lymphocytes (T and B cells), with huge specificity towards its targets and immunological memory. On the contrary, the innate immune system is activated quickly and nonspecifically in response to foreign pathogens or damaged self [91, 92].
There are two crucial lymphocytes called T and B lymphocytes in the human body. Tumor-infiltrating B cells can produce antitumor effects not only by the production of tumor-specific antibodies and stimulation of T cell responses, but also by sustaining the tertiary lymphoid structure. [93]. Cytotoxic intra-tumoral CD4+ T cells have been found to kill cancer cells directly in preclinical and clinical trials. [94]. The CD4+ T helper cells and CD8+ cytotoxic T lymphocytes are two different subgroups of T cells divided on their function [95]. Three mechanisms that induce apoptosis in target cells include the secretion of proinflammatory cytokines, the interaction of the Fas ligand and Fas receptor, and the release of cytolytic granules containing perforin [96]. By regulating the activity of other immune cells like macrophages, neutrophils, B cells and CTLs, CD4+ T cells indirectly contribute in the removal of infections [97, 98]. By stimulating the proliferation of T and B cells as well as increasing the production of IgA, IgG, IgM, IFN-γ, interleukin-2 (IL-2), interleukin-6 (IL-6), complement 3, complement 4 and TNF-α, ASPC (8 mg/kg) was shown to improve immunity in cyclophosphamide-induced immunosuppressive mice in vivo [99]. Based on studies, APS could influence the growth of tumors in melanoma-bearing mice. It might decrease the quantity of myeloid-derived suppressor cells (MDSCs) and the expression of the cytokines IL-10 and TGF-β and the MDSC-related molecule Arg-1, which allowed CD8+ T cells to kill tumor cells more effectively [100]. Through activating antitumor immune cells and regulating the percentages of CD3+, CD4+, CD8+ T cells and CD19 B cells in tumor-bearing mice, APS have been found to be practical as a supplement for immune enhancement that can promote anaerobic metabolism of the TME and cell apoptosis [101]. Selenium-containing polysaccharides from the roots of astragalus membranaceus reduced CD4+ T cell apoptosis and serum cytokine dysregulation caused by tumor transplantation, which promoted the cytotoxic activities of NK cells and CD8+ T cells [102]. CD4+CD25+ Treg cell is known as a kind of T cells with immunosuppressive effect that can prevent the activation and proliferation of T cells [103, 104]. In the human hepatocellular carcinoma, APS can relieve the immune-suppressive effects of Treg cells by restoring the balance of cytokines in the TME, suppressing the expression of FOXp3 mRNA or inhibiting Treg cell migration by blocking SDF-1 and its receptor via the CXCR4/CXCL12 pathway [105]. The experiment has shown that APS could stimulate the proliferation of B cells which extracted from mouse spleen and cultured in vitro, but it is not sensitive to the proliferation of T cells [106]. The joint application of Chinese herbal extracts demonstrated additional benefits. In mice with lung cancer, the combination of the polysaccharopeptide (PSP) and APS dramatically improved the level of WBC, thymus index, spleen index, CD4/CD8 ratio, TNF, IFN-γ, IL-2 and interleukin-17 (IL-17), which indicated their immunomodulatory effects and antitumor activity [107]. In summary, by accelerating the proliferation of T and B cells, increasing the release of associated cytokines and suppressing the function of Treg cells, APS can improve immunosuppression and strengthen tumor immunity (Fig. 1).
3 Application of Astragalus polysaccharides combined with immunotherapy
Currently, cancer immunotherapies approved by Food and Drug Administration (FDA) roughly included interferon, interleukin-2, dendritic cell vaccine, chimeric antigen receptor-T cells, anti-cytotoxic T lymphocyte antigen-4, anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies, and so on [12]. APS has been demonstrated to improve the effect of immunotherapy in vivo and in vitro experiments [108, 109]. For example, by the AKT/mTOR/p70S6K pathway, PG2 can decrease the expression of PD-L1 on the cell surface, which may improve the efficacy of chemotherapy, and also decrease the expression of indoleamine 2, 3-dioxygenase 1 in tumor cells [109]. In an animal experiment on mice, APS can maintain an effective dose of anti-PD-1 antibodies in the body and can slow the tumor progression and genesis by boosting the activity of T cells. These findings may indicate that APS can enhance immune regulation or can be used as a supplement to therapy [110]. The cell experiment in vitro found that an appropriate dose of APS could upregulate the high expression of HLA-DR, CD86 and other co-stimulatory molecules related to antigen presentation on the surface of DC membrane, which had a significant effect on promoting DC differentiation and maturation, and increased the immune activity of DC [111]. By synergizing the cytotoxicity of cytokine-induced killer cells, APS can have cytotoxic effects on tumor cells. These are the same applied in lung cancer, cervical cancer, ovarian cancer and many other tumors [112,113,114]. To sum up, it is expected that APS will play an important role in the immunotherapy in the future.
4 Application of APS in gastrointestinal tumors
4.1 Application of APS in gastric cancer
Apoptosis induction: It has been shown that APS4 can induce MGC-803 cells apoptosis by promoting poly-ADP-ribose polymerase (PARP) cleavage and activating the expression of caspase 9/3, which result in accumulating intracellular ROS, releasing cytochrome c, increasing the expression of Bax and decreasing the expression of Bcl-2 [115]. With increasing the expression of caspase 3 that caused DNA fragmentation and promoting the expression of tumor suppressor genes via the MAPK signaling pathway, APS caused both the apoptosis of SGC-7901 cells and adriamycin resistant SGC-7901 cells [116]. Proliferation inhibition: SC-B, components of which are schisandrin B, aloe-emodin and APS, can restrict the proliferation and abnormal mitosis of human gastric cancer SCG-7901 cells in vitro. The inhibitory effect that leads to the cell cycle arrest of gastric cancer cells may be related to the decreased expression of cyclin D1 mRNA [117]. Enhancement of the anticancer effect of anticancer medicines: APS increased the anticancer effects of apatinib on gastric cancer AGS cells by lowering the levels of phosphorylated AKT and MMP-9 in the AKT signaling pathway [118]. Improvement of clinical efficacy and relief of chemotherapy adverse reactions: For patients with gastric cancer, the combination of the APS injection and the FOLFOX regimen (which consists of oxaliplatin, calcium folinate and 5 fluorouracil) seemed to be the most effective in terms of clinical efficacy as well as in relieving adverse reactions, particularly in leucopenia and gastrointestinal reaction [119].
4.2 Application of APS in colorectal cancer
Proliferation inhibition: PG2 is a polysaccharide, isolated from the radix astragali, that suppresses the production and function of PD-L1 in tumors by the AKT/mTOR/p70S6K signaling pathway. With the combination of cisplatin and PG2, the growth of the mouse breast tumor and colorectal tumor was dramatically slowed [109]. Immunoactivity regulation: Effective antibodies, like anti-PD1 and anti-VEGF, can be generated by using APS that induces somatic mutation reaction in vivo. That may further enhance the antitumor immunity [110, 120].
4.3 Application of APS in liver cancer
Enhancement of chemosensitivity: APS can improve the chemosensitivity of Adriamycin-resistant H22 hepatoma cells. This may be related to the down-regulation of MDR1 mRNA, the inhibition of P-GP efflux pump function, which would lower the expression of the MDR1 protein [121]. Furthermore, by activating the JNK pathway, APS could enhance the sensitivity of SKOV3 cells to cisplatin, which is related to the apoptosis-related genes [122]. Immunoactivity regulation: To prevent the immunosuppressive effect of Treg cells, APS may restore the balance of cytokines in the TME and reduce the production of FOXp3 mRNA, which may enhance the antitumor effects of the immunotherapy-based methods [105]. In addition, by the miR-133a-3p/MSN axis, APS may also decrease the PD-L1-mediated immunosuppression, which leads to an anticancer effect [123]. Experiments of the hepatocellular carcinoma H22-bearing mice have showed that by raising the spleen and thymus indexes as well as increasing the cytokines like IL-2, IL-6, and TNF-α in serum, APS can affect immune-regulating features in tumor. In addition, APS increased the expression of the proteins Bax and decreased the expression of Bcl-2, which are related to the cell survival or death [53, 124, 125]. Relief of chemotherapy adverse reactions: APS can reduce the liver damage brought by cantharidin, which is involved in regulating bile acid biosynthesis and glycerophospholipid metabolism [126]. Additionally, APS is also effective in relieving the hepatotoxicity in mice that is caused by common chemotherapy drugs, such as cyclophosphamide, docetaxel and epirubicin [127] (Fig. 2 and Table 1).
5 Summary and outlook
At present, the popular tumor treatments are composed of radiotherapy, chemotherapy and surgery while immunotherapy and targeted therapy also show great development prospects. Immunotherapy in tumor mainly includes immune checkpoint inhibitors, cancer vaccines, adoptive cellular therapy, NK cell and CAR T cell therapy, etc. [128,129,130,131]. Yet, there is still a lot to be done for research.
APS and its related preparations have long been used clinically. Among them, APS is the most eye-catching in terms of immune regulation. APS can regulate the activity of diverse immune cells and further improve the TIME. Macrophages, NK cells, DCs, T cells and B cells are some of these immune cells. Moreover, APS can stimulate the production of various cytokines and chemokines generated by these immune cells, which strengthen the immunological response. Right now, researches on using APS to enhance immunomodulation or to be one complement of the treatment are in progress. We currently have a limited knowledge of the effects and the mechanisms that APS works in anti-tumor therapy. We need to deeper explore the mechanism of action of APS and related targets. However, we also require more explanation of its principle in antiaging, antitumor, antifibrosis, antibacterial and antiviral. APS is used in improving the immune functions of patients treated by chemical therapy or radiation therapy. One of the important factors in the prevention and treatment of diseases is the dose–response relationship [11]. Thus, more researches are essential to accurately control the dosage of APS that will make the most of its benefits. Hopefully, APS will be a strong ally in tumor immunotherapy with the advancement of clinical trials and combination medication researches.
Data Availability
Not applicable.
References
Liu P, Zhao H, Luo Y. Anti-aging implications of Astragalus membranaceus (Huangqi): a well-known chinese tonic. Aging Dis. 2017;8(6):868–86. https://doi.org/10.14336/AD.2017.0816.
Auyeung KK, Han QB, Ko JK. Astragalus membranaceus: a review of its protectionagainst inflammation and gastrointestinal cancers. Am J Chin Med. 2016;44(1):1–22. https://doi.org/10.1142/S0192415X16500014.
Shahzad M, Shabbir A, Wojcikowski K, Wohlmuth H, Gobe GC. The antioxidant effects of radix astragali (Astragalus membranaceus and related species) in protecting tissues from injury and disease. Curr Drug Targets. 2016;17(12):1331–40. https://doi.org/10.2174/1389450116666150907104742.
Zhang Q, Liu J, Duan H, Li R, Peng W, Wu C. Activation of Nrf2/HO-1 signaling: an important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J Adv Res. 2021;6(34):43–63. https://doi.org/10.1016/j.jare.2021.06.023.
Fu J, Wang Z, Huang L, Zheng S, Wang D, Chen S, Zhang H, Yang S. Review of the botanical characteristics, phytochemistry, and pharmacology of Astragalus membranaceus (Huangqi). Phytother Res. 2014;28(9):1275–83. https://doi.org/10.1002/ptr.5188.
Zhang J, Wu C, Gao L, Du G, Qin X. Astragaloside IV derived from Astragalus membranaceus: a research review on the pharmacological effects. Adv Pharmacol. 2020;87:89–112. https://doi.org/10.1016/bs.apha.2019.08.002.
Tang Z, Huang G. Extraction, structure, and activity of polysaccharide from Radix astragali. Biomed Pharmacother. 2022;150:113015. https://doi.org/10.1016/j.biopha.2022.113015.
Zheng Y, Ren W, Zhang L, Zhang Y, Liu D, Liu Y. A review of the pharmacological action of Astragalus polysaccharide. Front Pharmacol. 2020;24(11):349. https://doi.org/10.3389/fphar.2020.00349.
Kong F, Chen T, Li X, Jia Y. The current application and future prospects of Astragalus Polysaccharide combined with cancer immunotherapy: a review. Front Pharmacol. 2021;12:737674. https://doi.org/10.3389/fphar.2021.737674.
Du X, Zhao B, Li J, Cao X, Diao M, Feng H, Chen X, Chen Z, Zeng X. Astragalus polysaccharides enhance immune responses of HBV DNA vaccination via promoting the dendritic cell maturation and suppressing Treg frequency in mice. Int Immunopharmacol. 2012;14(4):463–70. https://doi.org/10.1016/j.intimp.2012.09.006.
Shao P, Zhao LH, Zhi-Chen Pan JP. Regulation on maturation and function of dendritic cells by Astragalus mongholicus polysaccharides. Int Immunopharmacol. 2006;6(7):1161–6. https://doi.org/10.1016/j.intimp.2006.02.009.
Liu QY, Yao YM, Yu Y, Dong N, Sheng ZY. Astragalus polysaccharides attenuate postburn sepsis via inhibiting negative immunoregulation of CD4+ CD25(high) T cells. PLoS One. 2011; 6(6): e19811. doi: https://doi.org/10.1371/journal.pone.0019811. Epub 2011 Jun 15. Erratum in: PLoS One. 2011; 6(7). doi:https://doi.org/10.1371/annotation/6c65352a-a393-4130-98b4-9a39793723d6.
Hou YC, Wu JM, Wang MY, Wu MH, Chen KY, Yeh SL, Lin MT. Modulatory effects of astragalus polysaccharides on T-cell polarization in mice with polymicrobial sepsis. Mediators Inflamm. 2015;2015:826319. https://doi.org/10.1155/2015/826319.
Shao BM, Xu W, Dai H, Tu P, Li Z, Gao XM. A study on the immune receptors for polysaccharides from the roots of Astragalus membranaceus, a Chinese medicinal herb. Biochem Biophys Res Commun. 2004;320(4):1103–11. https://doi.org/10.1016/j.bbrc.2004.06.065.
Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):396. https://doi.org/10.1186/s13046-019-1396-4.
Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y, Hu J, Chen K. Single-cell RNAsequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun. 2020;11(1):5077. https://doi.org/10.1038/s41467-020-18916-5.
Zavros Y, Merchant JL. The immune microenvironment in gastric adenocarcinoma. Nat Rev Gastroenterol Hepatol. 2022;19(7):451–67. https://doi.org/10.1038/s41575-022-00591-0.
Becerril-Rico J, Alvarado-Ortiz E, Toledo-Guzmán ME, Pelayo R, Ortiz-Sánchez E. The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor. Stem Cell Res Ther. 2021;12(1):498. https://doi.org/10.1186/s13287-021-02562-9.
Fu L, Bu L, Yasuda T, Koiwa M, Akiyama T, Uchihara T, Baba H, Ishimoto T. Gastric cancer stem cells: current insights into the immune microenvironment and therapeutic targets. Biomedicines. 2020;8(1):7. https://doi.org/10.3390/biomedicines8010007.
Oya Y, Hayakawa Y, Koike K. Tumor microenvironment in gastric cancers. Cancer Sci. 2020;111(8):2696–707. https://doi.org/10.1111/cas.14521.
Gupta RG, Li F, Roszik J, Lizée G. Exploiting tumor neoantigens to target cancer evolution: current challenges and promising therapeutic approaches. Cancer Discov. 2021;11(5):1024–39. https://doi.org/10.1158/2159-8290.CD-20-1575.
van den Ende T, van den Boorn HG, Hoonhout NM, van Etten-Jamaludin FS, Meijer SL, Derks S, de Gruijl TD, Bijlsma MF, van Oijen MGH, van Laarhoven HWM. 2020 Priming the tumor immune microenvironment with chemo(radio)therapy: a systematic review acrosstumor types. Biochim Biophys Acta Rev Cancer. 2020;1874(1):188386. https://doi.org/10.1016/j.bbcan.2020.188386.
Huang X, Han L, Wang R, Zhu W, Zhang N, Qu W, Liu W, Liu F, Feng F, Xue J. Dual-responsive nanosystem based on TGF-β blockade and immunogenic chemotherapy for effective chemoimmunotherapy. Drug Deliv. 2022;29(1):1358–69. https://doi.org/10.1080/10717544.2022.2069877.
Zhao Y, Pan Y, Zou K, Lan Z, Cheng G, Mai Q, Cui H, Meng Q, Chen T, Rao L, Ma L, Yu G. Biomimetic manganese-based theranostic nanoplatform for cancer multimodal imaging and twofold immunotherapy. Bioact Mater. 2022;20(19):237–50. https://doi.org/10.1016/j.bioactmat.2022.04.011.
Liu Z, Zhou Z, Dang Q, Xu H, Lv J, Li H, Han X. Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy. Theranostics. 2022;12(14):6273–90. https://doi.org/10.7150/thno.76854.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.
Feng Y, Ma F, Wu E, Cheng Z, Wang Z, Yang L, Zhang J. Ginsenosides: allies of gastrointestinal tumor immunotherapy. Front Pharmacol. 2022;13:922029. https://doi.org/10.3389/fphar.2022.922029.
Gourd K. ESMO world congress on gastrointestinal cancer 2021. Lancet Oncol. 2021;22(8):1062. https://doi.org/10.1016/S1470-2045(21)00395-8.
Li CX, Liu Y, Zhang YZ, Li JC, Lai J. Astragalus polysaccharide: a review of its immunomodulatory effect. Arch Pharm Res. 2022;45(6):367–89. https://doi.org/10.1007/s12272-022-01393-3.
Chen L, He C, Zhou M, Long J, Li L. Research progress on the mechanisms of polysaccharides against gastric cancer. Molecules. 2022;27(18):5828. https://doi.org/10.3390/molecules27185828.
Hume DA. The mononuclear phagocyte system. Curr Opin Immunol. 2006;18(1):49–53. https://doi.org/10.1016/j.coi.2005.11.008.
Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv Drug Deliv Rev. 2017;15(114):206–21. https://doi.org/10.1016/j.addr.2017.04.010.
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61. https://doi.org/10.1016/j.immuni.2014.06.010.
Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015;212(4):435–45. https://doi.org/10.1084/jem.20150295.
Sun X, Gao D, Gao L, Zhang C, Yu X, Jia B, Wang F, Liu Z. Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer. Theranostics. 2015;5(6):597–608. https://doi.org/10.7150/thno.11546.
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96. https://doi.org/10.1038/ni.1937.
DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19(6):369–82. https://doi.org/10.1038/s41577-019-0127-6.
Mantovani A, Locati M. Tumor-associated macrophages as a paradigm of macrophageplasticity, diversity, and polarization: lessons and open questions. Arterioscler Thromb Vasc Biol. 2013;33(7):1478–83. https://doi.org/10.1161/ATVBAHA.113.300168.
Pan Y, Yu Y, Wang X, Zhang T. Tumor-associated macrophages in tumor immunity. Front Immunol. 2020;11:583084. https://doi.org/10.3389/fimmu.2020.583084.
Wang HW, Joyce JA. Alternative activation of tumor-associated macrophages by IL-4: priming for protumoral functions. Cell Cycle. 2010;9(24):4824–35. https://doi.org/10.4161/cc.9.24.14322.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37. https://doi.org/10.1038/nm.3394.
Caux C, Ramos RN, Prendergast GC, Bendriss-Vermare N, Ménétrier-Caux C. A milestone review on how macrophages affect tumor growth. Cancer Res. 2016;76(22):6439–42. https://doi.org/10.1158/0008-5472.CAN-16-2631.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55. https://doi.org/10.1016/s1471-4906(02)02302-5.
Chen D, Zhang X, Li Z, Zhu B. Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages. Theranostics. 2021;11(3):1016–30. https://doi.org/10.7150/thno.51777.
Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer. Trends Immunol. 2019;40(4):310–27. https://doi.org/10.1016/j.it.2019.02.003.
Han S, Wang W, Wang S, Yang T, Zhang G, Wang D, Ju R, Lu Y, Wang H, Wang L. Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes. Theranostics. 2021;11(6):2892–916. https://doi.org/10.7150/thno.50928.
Wei W, Li ZP, Bian ZX, Han QB. Astragalus polysaccharide RAP induces macrophage phenotype polarization to M1 via the notch signaling pathway. Molecules. 2019;24(10):2016. https://doi.org/10.3390/molecules24102016.
Bamodu OA, Kuo KT, Wang CH, Huang WC, Wu ATH, Tsai JT, Lee KY, Yeh CT, Wang LS. Astragalus polysaccharides (PG2) enhances the M1 polarization of macrophages, functional maturation of dendritic cells, and T cell-mediated anticancer immune responses in patients with lung cancer. Nutrients. 2019;11(10):2264. https://doi.org/10.3390/nu11102264.
Li W, Song K, Wang S, Zhang C, Zhuang M, Wang Y, Liu T. Anti-tumor potential of astragalus polysaccharides on breast cancer cell line mediated by macrophage activation. Mater Sci Eng C Mater Biol Appl. 2019;98:685–95. https://doi.org/10.1016/j.msec.2019.01.025.
Zhou L, Liu Z, Wang Z, Yu S, Long T, Zhou X, Bao Y. Astragalus polysaccharides exerts immunomodulatory effects via TLR4-mediated MyD88-dependent signaling pathway in vitro and in vivo. Sci Rep. 2017;17(7):44822. https://doi.org/10.1038/srep44822.
Zhao LH, Ma ZX, Zhu J, Yu XH, Weng DP. Characterization of polysaccharide from Astragalus radix as the macrophage stimulator. Cell Immunol. 2011;271(2):329–34. https://doi.org/10.1016/j.cellimm.2011.07.011.
Li W, Hu X, Wang S, Jiao Z, Sun T, Liu T, Song K. Characterization and anti-tumor bioactivity of astragalus polysaccharides by immunomodulation. Int J Biol Macromol. 2020;15(145):985–97. https://doi.org/10.1016/j.ijbiomac.2019.09.189.
Yang B, Xiao B, Sun T. Antitumor and immunomodulatory activity of Astragalus membranaceus polysaccharides in H22 tumor-bearing mice. Int J Biol Macromol. 2013;62:287–90. https://doi.org/10.1016/j.ijbiomac.2013.09.016.
Verneau J, Sautés-Fridman C, Sun CM. Dendritic cells in the tumor microenvironment: prognostic and theranostic impact. Semin Immunol. 2020;48:101410. https://doi.org/10.1016/j.smim.2020.101410.
Tang KT, Chen HH, Chen TT, Bracci NR, Lin CC. Dendritic cells and antiphospholipid syndrome: an updated systematic review. Life (Basel). 2021;11(8):801. https://doi.org/10.3390/life11080801.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811. https://doi.org/10.1146/annurev.immunol.18.1.767.
Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, Helft J, Ochando J, Kissenpfennig A, Malissen B, Grisotto M, Snoeck H, Randolph G, Merad M. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med. 2007;204(13):3133–46. https://doi.org/10.1084/jem.20071733.
Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307(5707):254–8. https://doi.org/10.1126/science.1102901.
Kambayashi T, Laufer TM. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol. 2014;14(11):719–30. https://doi.org/10.1038/nri3754.
Worbs T, Hammerschmidt SI, Förster R. Dendritic cell migration in health and disease. Nat Rev Immunol. 2017;17(1):30–48. https://doi.org/10.1038/nri.2016.116.
Hasegawa H, Matsumoto T. Mechanisms of tolerance induction by dendritic cells in vivo. Front Immunol. 2018;26(9):350. https://doi.org/10.3389/fimmu.2018.00350.
Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front Immunol. 2019;21(9):3176. https://doi.org/10.3389/fimmu.2018.03176.
Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U, Murphy KM, Schreiber RD. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011;208(10):1989–2003. https://doi.org/10.1084/jem.20101158.
Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 2011;208(10):2005–16. https://doi.org/10.1084/jem.20101159.
Liu Y, Cao X. Intratumoral dendritic cells in the anti-tumor immune response. Cell Mol Immunol. 2015;12(4):387–90. https://doi.org/10.1038/cmi.2014.130.
Zong J, Keskinov AA, Shurin GV, Shurin MR. Tumor-derived factors modulating dendritic cell function. Cancer Immunol Immunother. 2016;65(7):821–33. https://doi.org/10.1007/s00262-016-1820-y.
Conejo-Garcia JR, Rutkowski MR, Cubillos-Ruiz JR. State-of-the-art of regulatory dendritic cells in cancer. Pharmacol Ther. 2016;164:97–104. https://doi.org/10.1016/j.pharmthera.2016.04.003.
Tang M, Diao J, Cattral MS. Molecular mechanisms involved in dendritic cell dysfunction in cancer. Cell Mol Life Sci. 2017;74(5):761–76. https://doi.org/10.1007/s00018-016-2317-8.
Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z, Egeblad M, Krummel MF. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell. 2012;21(3):402–17. https://doi.org/10.1016/j.ccr.2012.01.008.
Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, de Chaisemartin L, Ouakrim H, Becht E, Alifano M, Validire P, Remark R, Hammond SA, Cremer I, Damotte D, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74(3):705–15. https://doi.org/10.1158/0008-5472.CAN-13-1342.
Wang D, Cui Q, Yang YJ, Liu AQ, Zhang G, Yu JC. Application of dendritic cells in tumor immunotherapy and progress in the mechanism of anti-tumor effect of Astragalus polysaccharide (APS) modulating dendritic cells: a review. Biomed Pharmacother. 2022;155:113541. https://doi.org/10.1016/j.biopha.2022.113541.
Zhu N, Lv X, Wang Y, Li J, Liu Y, Lu W, Yang L, Zhao J, Wang F, Zhang LW. Comparison of immunoregulatory effects of polysaccharides from three natural herbs and cellular uptake in dendritic cells. Int J Biol Macromol. 2016;93(Pt A):940–51. https://doi.org/10.1016/j.ijbiomac.2016.09.064.
Lim SM, Park HB, Jin JO. Polysaccharide from Astragalus membranaceus promotes the activation of human peripheral blood and mouse spleen dendritic cells. Chin J Nat Med. 2021;19(1):56–62. https://doi.org/10.1016/S1875-5364(21)60006-7.
Liu QY, Yao YM, Zhang SW, Sheng ZY. Astragalus polysaccharides regulate T cell-mediated immunity via CD11c(high)CD45RB(low) DCs in vitro. J Ethnopharmacol. 2011;136(3):457–64. https://doi.org/10.1016/j.jep.2010.06.041.
Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer. 1975;16(2):230–9. https://doi.org/10.1002/ijc.2910160205.
Pfefferle A, Jacobs B, Haroun-Izquierdo A, Kveberg L, Sohlberg E, Malmberg KJ. Deciphering natural killer cell homeostasis. Front Immunol. 2020;12(11):812. https://doi.org/10.3389/fimmu.2020.00812.
Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633–40. https://doi.org/10.1016/s1471-4906(01)02060-9.
Björkström NK, Ljunggren HG, Michaëlsson J. Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol. 2016;16(5):310–20. https://doi.org/10.1038/nri.2016.34.
Battella S, Cox MC, Santoni A, Palmieri G. Natural killer (NK) cells and anti-tumor therapeutic mAb: unexplored interactions. J Leukoc Biol. 2016;99(1):87–96. https://doi.org/10.1189/jlb.5VMR0415-141R.
Kim N, Lee HH, Lee HJ, Choi WS, Lee J, Kim HS. Natural killer cells as a promising therapeutic target for cancer immunotherapy. Arch Pharm Res. 2019;42(7):591–606. https://doi.org/10.1007/s12272-019-01143-y.
López-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of metastasis by NK Cells. Cancer Cell. 2017;32(2):135–54. https://doi.org/10.1016/j.ccell.2017.06.009.
Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, Griffero F, Marubbi D, Spaziante R, Bellora F, Moretta L, Moretta A, Corte G, Bottino C. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol. 2009;182(6):3530–9. https://doi.org/10.4049/jimmunol.0802845.
Pietra G, Manzini C, Vitale M, Balsamo M, Ognio E, Boitano M, Queirolo P, Moretta L, Mingari MC. Natural killer cells kill human melanoma cells with characteristics of cancer stem cells. Int Immunol. 2009;21(7):793–801. https://doi.org/10.1093/intimm/dxp047.
Yong AS, Keyvanfar K, Hensel N, Eniafe R, Savani BN, Berg M, Lundqvist A, Adams S, Sloand EM, Goldman JM, Childs R, Barrett AJ. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood. 2009;113(4):875–82. https://doi.org/10.1182/blood-2008-05-158253.
Mentlik James A, Cohen AD, Campbell KS. Combination immune therapies to enhance anti-tumor responses by NK cells. Front Immunol. 2013;23(4):481. https://doi.org/10.3389/fimmu.2013.00481.
Chretien AS, Le Roy A, Vey N, Prebet T, Blaise D, Fauriat C, Olive D. Cancer-induced alterations of NK-mediated target recognition: current and investigational pharmacological strategies aiming at restoring NK-mediated anti-tumor activity. Front Immunol. 2014;24(5):122. https://doi.org/10.3389/fimmu.2014.00122.
Zingoni A, Fionda C, Borrelli C, Cippitelli M, Santoni A, Soriani A. Natural killer cell response to chemotherapy-stressed cancer cells: role in tumor immunosurveillance. Front Immunol. 2017;25(8):1194. https://doi.org/10.3389/fimmu.2017.01194.
Mu JY, Li YD, Zhao XK, Li J, Yang AJ. Astragalus polysaccharide restores activation of NK cells in radiation therapy of tumors. Int J Clin Exp Med. 2019;12:8609–21.
Li CS, Talapphet N, Palanisamy S, Ma N, Cho ML, You S. The relationship between structural properties and activation of RAW264.7 and natural killer (NK) cells by sulfated polysaccharides extracted from Astragalus membranaceus roots. Process Biochem. 2020;97:140–8. https://doi.org/10.1016/j.procbio.2020.06.021.
Hwang J, Zhang W, Dhananjay Y, An EK, Kwak M, You S, Lee PC, Jin JO. Astragalus membranaceus polysaccharides potentiate the growth-inhibitory activity of immune checkpoint inhibitors against pulmonary metastatic melanoma in mice. Int J Biol Macromol. 2021;1(182):1292–300. https://doi.org/10.1016/j.ijbiomac.2021.05.073.
Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012;249(1):158–75. https://doi.org/10.1111/j.1600-065X.2012.01146.x.
Wik JA, Skålhegg BS. T cell metabolism in infection. Front Immunol. 2022;13:840610. https://doi.org/10.3389/fimmu.2022.840610.
Wang SS, Liu W, Ly D, Xu H, Qu L, Zhang L. Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. Cell Mol Immunol. 2019;16(1):6–18. https://doi.org/10.1038/s41423-018-0027-x.
Oh DY, Fong L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity. 2021;54(12):2701–11. https://doi.org/10.1016/j.immuni.2021.11.015.
Ostroumov D, Fekete-Drimusz N, Saborowski M, Kühnel F, Woller N. CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci. 2018;75(4):689–713. https://doi.org/10.1007/s00018-017-2686-7.
Schmidt ME, Varga SM. The CD8 T cell response to respiratory virus infections. Front Immunol. 2018;9(9):678. https://doi.org/10.3389/fimmu.2018.00678.
Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89. https://doi.org/10.1146/annurev-immunol-030409-101212.
Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557–69. https://doi.org/10.1182/blood-2008-05-078154.
Meng F, Xu P, Wang X, Huang Y, Wu L, Chen Y, Teng L, Wang D. Investigation on the immunomodulatory activities of Sarcodon imbricatus extracts in a cyclophosphamide (CTX)-induced immunosuppressanted mouse model. Saudi Pharm J. 2017;25(4):460–3. https://doi.org/10.1016/j.jsps.2017.04.006.
Ding G, Gong Q, Ma J, Liu X, Wang Y, Cheng X. Immunosuppressive activity is attenuated by Astragalus polysaccharides through remodeling the gut microenvironment in melanoma mice. Cancer Sci. 2021;112(10):4050–63. https://doi.org/10.1111/cas.15078.
Yu J, Dong XD, Jiao JS, Ji HY, Liu AJ. Antitumor and immunoregulatory activities of a novel polysaccharide from Astragalus membranaceus on S180 tumor-bearing mice. Int J Biol Macromol. 2021;31(189):930–8. https://doi.org/10.1016/j.ijbiomac.2021.08.099.
Li S, Bian F, Yue L, Jin H, Hong Z, Shu G. Selenium-dependent antitumor immunomodulating activity of polysaccharides from roots of A. membranaceus. Int J Biol Macromol. 2014;69:64–72. https://doi.org/10.1016/j.ijbiomac.2014.05.020.
Shi HZ, Qin XJ. CD4CD25 regulatory T lymphocytes in allergy and asthma. Allergy. 2005;60(8):986–95. https://doi.org/10.1111/j.1398-9995.2005.00844.x.
Dao Nguyen X, Robinson DS. Fluticasone propionate increases CD4CD25 T regulatory cell suppression of allergen-stimulated CD4CD25 T cells by an IL-10-dependent mechanism. J Allergy Clin Immunol. 2004;114(2):296–301. https://doi.org/10.1016/j.jaci.2004.04.048.
Li Q, Bao JM, Li XL, Zhang T, Shen XH. Inhibiting effect of Astragalus polysaccharides on the functions of CD4+CD25 highTreg cells in the tumor microenvironment of human hepatocellular carcinoma. Chin Med J (Engl). 2012;125(5):786–93.
Niu Y, Wang H, Xie Z, Whent M, Gao X, Xian Z, Zou S, Yao W, Yu L. Structural analysis and bioactivity of a polysaccharide from the roots of Astragalus membranaceus (Fisch) Bge. Var. mongolicus (Bge.) Hsiao. Food Chem. 2011;128:620–6. https://doi.org/10.1016/j.foodchem.2011.03.055.
Zhou X, Liu Z, Long T, Zhou L, Bao Y. Immunomodulatory effects of herbal formula of astragalus polysaccharide (APS) and polysaccharopeptide (PSP) in mice with lung cancer. Int J Biol Macromol. 2018;106:596–601. https://doi.org/10.1016/j.ijbiomac.2017.08.054.
Tsao SM, Wu TC, Chen J, Chang F, Tsao T. Astragalus polysaccharide injection (PG2) normalizes the neutrophil-to-lymphocyte ratio in patients with advanced lung cancer receiving immunotherapy. Integr Cancer Ther. 2021;20:1534735421995256. https://doi.org/10.1177/1534735421995256.
Chang HL, Kuo YH, Wu LH, Chang CM, Cheng KJ, Tyan YC, Lee CH. The extracts of Astragalus membranaceus overcome tumor immune tolerance by inhibition of tumor programmed cell death protein ligand-1 expression. Int J Med Sci. 2020;17(7):939–45. https://doi.org/10.7150/ijms.42978.
Chang FL, Tsai KC, Lin TY, Yang TW, Lo YN, Chen WC, Chang JH, Lu MK, Chiou CT, Chen PH, Yen Y, Pan SL, Lee YC. Astragalus membranaceus-derived anti-programmed death-1 monoclonal antibodies with immunomodulatory therapeutic effects against tumors. Biomed Res Int. 2020;3(2020):3415471. https://doi.org/10.1155/2020/3415471.
Chen CJ, Li ZL, Fu Q, Liu Y, Lei X, Wu HC, Liu YF. Effect of Astragalus polysaccharides on the phenotype and functions of human dendritic cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29(6):1192–4.
Zhang S, Mu X, Wang H, Jiang S. Enhancement of the cytotoxic effect of cytokine induced killers by dendritic cells pulsed with astragalus polysaccharides. Cell Mol Immunol. 2009;25(2):140–2.
Xu Y, Liu X, Qu F. Effects of Chinese medicine polysaccharides combined with adoptive immunotherapy on ovarian cancer. Chin J Exp Tradit Med Formulae. 2011;17(21):231–4. https://doi.org/10.13422/j.cnki.syfjx.2011.21.00.
Wang J, Han Q, Wang B, Yan X, Li W, Zhang M, et al. Effect of astragalus polysaccharide induced DCs co-cultured with CIK cells on Eca-109 cells. Acta Chin Med. 2016;31(4):478–81. https://doi.org/10.16368/j.issn.1674-8999.2016.04.136.
Yu J, Ji H, Dong X, Feng Y, Liu A. Apoptosis of human gastric carcinoma MGC-803 cells induced by a novel Astragalus membranaceus polysaccharide via intrinsic mitochondrial pathways. Int J Biol Macromol. 2019;1(126):811–9. https://doi.org/10.1016/j.ijbiomac.2018.12.268.
Song J, Chen Y, He D, Tan W, Lv F, Liang B, Xia T, Li J. Astragalus polysaccharide promotes adriamycin-induced apoptosis in gastric cancer cells. Cancer Manag Res. 2020;1(12):2405–14. https://doi.org/10.2147/CMAR.S237146.
Liu XN, Zhang CY, Jin XD, Li YZ, Zheng XZ, Li L. Inhibitory effect of schisandrin B on gastric cancer cells in vitro. World J Gastroenterol. 2007;13(48):6506–11. https://doi.org/10.3748/wjg.v13.i48.6506.
Wu J, Yu J, Wang J, Zhang C, Shang K, Yao X, Cao B. Astragalus polysaccharide enhanced antitumor effects of Apatinib in gastric cancer AGS cells by inhibiting AKT signalling pathway. Biomed Pharmacother. 2018;100:176–83. https://doi.org/10.1016/j.biopha.2018.01.140.
Zhang D, Zheng J, Ni M, Wu J, Wang K, Duan X, Zhang X, Zhang B. Comparative efficacy and safety of Chinese herbal injections combined with the FOLFOX regimen for treating gastric cancer in China: a network meta-analysis. Oncotarget. 2017;8(40):68873–89. https://doi.org/10.18632/oncotarget.20320.
Lee YC, Huang HT, Chang CD, Chen CT, Lin TY, Yang TW, Chang FL, Lu MK, Chiou CT, Chen WC, Pan SL, Tsai KC. Isolation of anti-VEGF monoclonal antibodies with neutralizing effects from an Astragalus-induced immune antibody library. Int Immunopharmacol. 2020;88:107007. https://doi.org/10.1016/j.intimp.2020.107007.
Tian QE, De Li H, Yan M, Cai HL, Tan QY, Zhang WY. Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro. BMC Complement Altern Med. 2012;11(12):94. https://doi.org/10.1186/1472-6882-12-94.
Li C, Hong L, Liu C, Min J, Hu M, Guo W. Astragalus polysaccharides increase the sensitivity of SKOV3 cells to cisplatin. Arch Gynecol Obstet. 2018;297(2):381–6. https://doi.org/10.1007/s00404-017-4580-9.
He L, Xu K, Niu L, Lin L. Astragalus polysaccharide (APS) attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis in HCC. Pharm Biol. 2022;60(1):1710–20. https://doi.org/10.1080/13880209.2022.2112963.
Lai X, Xia W, Wei J, Ding X. Therapeutic effect of Astragalus polysaccharides on hepatocellular carcinoma H22-bearing mice. Dose Response. 2017;15(1):1559325816685182. https://doi.org/10.1177/1559325816685182.
Tian QE, Li HD, Yan M, Cai HL, Tan QY, Zhang WY. Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice. World J Gastroenterol. 2012;18(47):7079–86. https://doi.org/10.3748/wjg.v18.i47.7079.
Huang X, Tang W, Lin C, Sa Z, Xu M, Liu J, Wang L, Li W, Chen Y, Yang C. Protective mechanism of Astragalus Polysaccharides against Cantharidin-induced liver injury determined in vivo by liquid chromatography/mass spectrometry metabolomics. Basic Clin Pharmacol Toxicol. 2021;129(1):61–71. https://doi.org/10.1111/bcpt.13585.
Liu W, Gao FF, Li Q, Lv JW, Wang Y, Hu PC, Xiang QM, Wei L. Protective effect of astragalus polysaccharides on liver injury induced by several different chemotherapeutics in mice. Asian Pac J Cancer Prev. 2014;15(23):10413–20. https://doi.org/10.7314/apjcp.2014.15.23.10413.
Pham T, Roth S, Kong J, Guerra G, Narasimhan V, Pereira L, Desai J, Heriot A, Ramsay R. An update on immunotherapy for solid tumors: a review. Ann Surg Oncol. 2018;25(11):3404–12. https://doi.org/10.1245/s10434-018-6658-4.
Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, Ye Z, Qian Q. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15(12):2548–60. https://doi.org/10.7150/ijbs.34213.
Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;24(16):223–49. https://doi.org/10.1146/annurev-pathol-042020-042741.
Sellars MC, Wu CJ, Fritsch EF. Cancer vaccines: building a bridge over troubled waters. Cell. 2022;185(15):2770–88. https://doi.org/10.1016/j.cell.2022.06.035.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
QX and WC wrote the manuscript, XX provided ideas, YO and JW drew the figure and table, YJ reviewed the manuscript, QX and WC and XX and YO and JW and YJ worked together to complete the article.
Corresponding author
Ethics declarations
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Xu, Q., Cheng, W., Wei, J. et al. Synergist for antitumor therapy: Astragalus polysaccharides acting on immune microenvironment. Discov Onc 14, 179 (2023). https://doi.org/10.1007/s12672-023-00798-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12672-023-00798-w