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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 245-253

Research advances of traditional Chinese medicine in cancer immunotherapy


1 The Research Centre of Integrative Cancer Medicine, Discipline of Integrated Chinese and Western Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
2 The Research Centre of Integrative Cancer Medicine, Discipline of Integrated Chinese and Western Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine; Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
3 The Research Centre of Integrative Cancer Medicine, Discipline of Integrated Chinese and Western Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine; Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China

Date of Submission09-May-2020
Date of Decision05-Nov-2020
Date of Acceptance19-Nov-2020
Date of Web Publication28-Dec-2020

Correspondence Address:
Prof. Zhiyu Wang
The Research Centre of Integrative Cancer Medicine, Discipline of Integrated Chinese and Western Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CMAC.CMAC_42_20

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  Abstract 


Tumorigenesis are closely associated with the immune function of the human body. Immunotherapy has emerged as a novel and promising treatment strategy in multiple malignancies in the 21st century. Traditional Chinese medicine (TCM) has been extensively used for cancer treatment in China and surrounding countries for it exerts efficient therapeutic effects with few side effects. In recent years, studies have demonstrated that TCM plays a unique and reliable role in regulating tumor immunity. TCM can enhance the antitumor immune response function by regulating the secretion of cytokines, reshaping the balance of immune cells, and regulating immune checkpoints to relieve the immunosuppression. In addition, TCM can reduce the side effects (e.g., cytokine storm) of cancer immunotherapy. Based on the current research of active immunotherapy and passive immunotherapy, this review summarizes the potential applications and existing problems of TCM in tumor immunotherapy. This review may be helpful in illuminating the scientific basis of TCM in tumor immunotherapy, promoting its internationalization, as well as shedding innovating new strategies for the development of tumor immunotherapy.

Keywords: Cytokine, immune balance, immune checkpoint, traditional Chinese medicine, tumor immunotherapy


How to cite this article:
Li J, Wang S, Wang N, Wang Z. Research advances of traditional Chinese medicine in cancer immunotherapy. Chin Med Cult 2020;3:245-53

How to cite this URL:
Li J, Wang S, Wang N, Wang Z. Research advances of traditional Chinese medicine in cancer immunotherapy. Chin Med Cult [serial online] 2020 [cited 2021 Jan 15];3:245-53. Available from: https://www.cmaconweb.org/text.asp?2020/3/4/245/305180




  Introduction Top


Immunotherapy is one of the main clinical therapeutic strategies for cancer treatment, especially in the metastatic stage. Cancer immunotherapy came into being in the late 19th century, but it has developed rapidly in the past 30 years. In 1967, Burnet first proposed the concept of immune surveillance.[1] In 1991, the clinical application of cytokine-induced killer cells (CIK) against tumors was first reported by Stanford University in the United States (US).[2] In the past few years, immunotherapy has been extensively applied in clinical settings and has achieved success in treating several types of malignant tumors. By the end of 2016, the US Food and Drug Administration had approved approximately 50 kinds of antibody drugs for cancer immunotherapy. Clinical studies[3] have suggested that the 4-year survival rate of cancer patients treated by immunotherapy, which resulted in complete remission (CR) or partial remission, can be as high as 58%, five times higher than that of chemotherapy treatment. Cancer immunotherapy strategies can be divided into the active and the passive. Active immunotherapy strategies include cytokine therapy, immune checkpoint inhibitor therapy, and tumor vaccine, while passive immunotherapy strategies consist of lymphokine-activated killer cells (LAK), tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor T-cells (CAR-T), T-cell receptor (TCR) chimeric T-cells (TCR-T), and CIK. The detailed process of passive immunotherapy is illustrated in [Figure 1]. Compared with the other treatments, cancer immunotherapy has wide-range application, good clinical prognosis, and significant survival trailing effect. Although significant advances have been made in clinical settings, there still exist several obstacles, such as low response rates and therapeutic resistance after initial benefit. These obstacles can be attributed to the instability of tumor genome. Multigene mutations in tumors lead to different gene phenotypes and immune-resistant molecule, which confuse the immune system and escape immune surveillance, resulting in the low response rate and drug resistance of immunotherapy. At present, the main obstacles of tumor immunotherapy include (1) how to enhance the lethality of antitumor effector cells and cytokines; (2) how to reverse the inhibitory effect of tumor cells on tumor effector cells; (3) how to mend the low response rates of tumor patients to immunotherapy; and (4) how to solve the drug-resistance issue of immunotherapy drugs.

There is no clear definition of immunotherapy in the theoretical system of traditional Chinese medicine (TCM). The understanding of immunity in TCM is mainly reflected in the term “healthy qi (正气),” according to which, “Sufficient healthy-qi inside the body will prevent the invasion of pathogenic factors,” “Evil-qi will come and become entrenched when healthy qi accumulation is insufficient,” and “Healthy-qi deficiency will lead to cancer.[4]” Nowadays, the functional activities of the human body, as well as its abilities to adapt to the external environment, to resist disease and dispel pathogens, and to regulate and repair, have been incorporated into “healthy qi” by modern TCM scholars. The functions of healthy qi in resisting harmful xenobiotics and regulating physiological homeostasis are consistent with the theories of immune defense, immune homeostasis, and immune surveillance in the modern medicine. Su Wen “Bao Ming Quan Xing Lun” (《素问·宝命全形论》 Basic Question “Discourse on Treasuring Life and Preserving Physical Appearance”) recorded that “life is tangible and can't be separated from Yin and Yang.” Su Wen “Sheng Qi Tong Tian Lun” (《素问·生气通天论》 Basic Questions “Discourse on how the Generative Qi Communicates with Heaven”) explained that “the foundation of life is based on Yin and Yang. When the Yin and Yang are in equilibrium, one will be mentally healthy.” In TCM theory, it is stated that human health is achieved only when the Yin and Yang regulations are dynamically balanced. The functions of the human body in identifying self-components and removing harmful xenobiotics to maintain physiological homeostasis are the important manifestations of Yin and Yang balance in the human body. For example, some immune cells and immune molecules can promote immunity, while others play feedback inhibitory effects on overactivated immune response, suggesting a close interaction balance between them. However, sufficient healthy qi is a prerequisite for maintaining the dynamic balance of Yin and Yang in the human body. Their balance will bring health, while their imbalance will result in sickness. TCM has been empirically employed in clinical settings for thousands of years. Modern researchers have demonstrated that TCM can enhance the immune function of the human body by regulating the secretion of cytokines, regulating the transduction of abnormal cell signals, promoting the proliferation and differentiation of effector cells, and reshaping Th1/Th2 balance as well as M1/M2 balance. With the continuous development of TCM, it is playing an increasingly important role in cancer immunotherapy.


  Classifications and Advances of Cancer Immunotherapy Top


Active immunotherapy

Cytokine therapy

Cytokines are the cornerstone of cancer immunity. Cytokines are highly active multifunctional soluble proteins which are mainly secreted by activated immune cells and play an intermediary role in tumor immunity. Common cytokines include lymphokines, mononuclear factors as well as various factors secreted by other cells. So far, the roles of interferon-a (IFN)-a, interleukin (IL)-2, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of advanced malignant melanoma and renal cell carcinoma have been clinically validated.[5] At present, efficient cytokines have been developed with the application of genetic bioengineering technology in the field of medicine. The immune response of the human body could be significantly enhanced by combining cytokines with tumor vaccines. For example, a new vaccine with stronger immunogenicity can be prepared by transfecting cytokine genes into tumor cells. In addition, when transferring cytokine genes into antitumor effector cells, the local cytokine concentrations in tumors are greatly increased and therefore they can activate the antitumor immune response more effectively.

Tumor vaccine

In the 19th century, William Coley had suggested the idea of finding suitable tumor cell antigens to prepare tumor vaccines for activating the immune system.[6] Tumor vaccines have higher specificity and less toxicity than traditional radiotherapy and chemotherapy. At present, tumor vaccines can be divided into four categories including whole-cell vaccines, tumor polypeptide vaccines, genetic engineering vaccines, and antibody tumor vaccines. Although tumor vaccines have great potential effects, it is still embryonic in clinical application. In the late 20th century, the Bacillus Calmette–Guerin (BCG) vaccine became the standard therapy for superficial bladder cancer in the United States.[7] However, it is not effective for nonmuscular invasive bladder cancer (NMIBC) as the recurrence rate is relatively high. Steinberg et al.[8] found that the quadruple immunotherapy of BCG (BCG, IFN, IL-2, and GM-CSF) exhibited a good therapeutic effect on NMIBC. The median recurrence time of 52 patients was 16.3 months, while the 1-year relapse-free survival rate and 2-year relapse-free survival rates were 55% and 53%, respectively. Kamat et al.[9] suggested that BCG combined with PD-1 inhibitor could achieve an enhanced antitumor activity in the high-risk subgroup of NMIBC patients, although the combination effect still needed investigation proof. The rapid developments of high-throughput sequencing technology and bioinformatic technology have created novel opportunities for tumor vaccine. In 2017, both the Dana–Farber Cancer Center in Boston and the University of Mainz in Germany generated tumor vaccines based on peptide fragments and RNA, respectively; both the vaccines effectively activated T cell-mediated immune response in about 60% of patients with advanced melanoma.[10],[11] In 2018, these two teams designed personalized tumor vaccines to treat refractory gliomas. The median overall survival (mOS) was lifted to be 16.8 months and 29 months. Altogether, the tumor vaccines have shown promising results in clinical practices.[12],[13]

Immune checkpoint inhibitor therapy

Immune checkpoint inhibitors reactivate immune signals by relieving the immunosuppressive effect of tumor cells, allowing T-cells to re-recognize and kill tumor cells. Immune checkpoint inhibitors are regarded as breakthrough treatments for multiple malignancies and have significantly enhanced the overall survival (OS) opportunity of patients with advanced malignancies. At present, the main immune checkpoint inhibitors that have been used in the clinical stage include anti-Cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and PD-1/L1 antibodies. Their representative drugs include pembrolizumab, nivolumab, and atezolizumab, which are mainly used in patients with unresectable or metastatic tumors or in patients with high microsatellite instability or mismatch repair defects.[14] In 2017, the combination regimen of pembrolizumab and pemetrexed/carboplatin was approved of as the first-line treatment regimen for advanced nonsmall cell lung cancer (NSCLC), regardless of PD-L1 expression status. Clinical studies demonstrated that the mOS of advanced NSCLC patients treated with nivolumab and atezolizumab was 9.2 and 20.5 months, respectively, which were 3.2 and 11.6 months longer than those in the docetaxel group.[15] Due to the broad anticancer spectrum and good prognosis, immune checkpoint inhibitors have revolutionized cancer therapy and have become the focus of clinical and basic research in recent years. Intensive efforts are being made to explore the underlying mechanisms of the existing immune checkpoint inhibitors, while more immune checkpoint inhibitors targeting new immunosuppressive checkpoint markers such as LAG3, TIM3, and VISTA are under way of development.

Passive immunotherapy

Lymphokine-activated killer cells and tumor-infiltrating lymphocytes

The precursors of LAK cells are natural killer (NK) cells, while the precursors of TIL cells are T-lymphocytes infiltrating in tumor tissues. Both of them can be amplified in vitro by IL-2 stimulation, and their antitumor effects are not major histocompatibility complex (MHC) restricted. The activated LAK cells can recognize and kill malignant cells without being restricted by specific tumor types. The proliferative response and anticancer effects of LAK cells are dependent on IL-2 dose. The antitumor activity of TIL cells is more lethal than LAK cells, but less dependent on IL-2 dose. Clinical studies have revealed that the complete response rate (CR) was 41% when melanoma patients with brain metastasis were treated with autologous TIL cells plus high-dose IL-2 (n = 17). For example, 5 of 17 patients had a treatment response duration ranging from 4 to 44 months, with an 8.5 months mOS, indicating that this treatment regimen can cause the complete and lasting regression of brain metastasis of melanoma.[16] Nowadays, the LAK and TIL cells are still under in-depth basic and clinical investigations. The main research directions include how to reduce the side effects of LAK and TIL cell therapy, how to activate their amplification, and gene modifications by transfecting with cytokine cDNA.

Cytokine-induced killer cells

CIK cells express both CD3+ and CD56+ membrane protein molecules, so they are also called NK cell-like T-lymphocytes. They exhibit both the antitumor activity of T-lymphocytes and the non-MHC-restricted tumor-killing activity of NK cells. CIK cells are highly proliferative, cytotoxic and can cleave or kill tumor cells by releasing perforin and granzymes, therefore resulting in host immunity improvement and suppression of the spread and recurrence of tumor cells. CIK cells have a wide antitumor spectrum and are widely used in the treatment of leukemia, lymphoma, and lung cancer. They are also effective on multidrug-resistant tumor cells. Luo et al.[17] reported that the advanced lung cancer patients treated with CIK have increased median progression-free survival (mPFS) (6 months vs. 4 months) and mOS (28 months vs. 22 months), compared with the best maintenance treatment group. Nowadays, CIK cell treatment is mainly used in cancer patients after surgery, radiotherapy, and chemotherapy. Cancer patients who are unable to receive routine treatment could also achieve good clinical outcomes through CIK treatment.

T-cell receptor chimeric T-cells and chimeric antigen receptor T-cells

TCR-T and CAR-T are the two major innovations in the adoptive cellular immunotherapy field at present. Genetically modified T-cells can express synthetic receptors and specifically recognize tumor cells. TCR-T utilizes MHC class I-restricted TCR technology to genetically modify CD8+ T-cells or bulk T-cells for patient treatments. Therefore, TCR-T is restricted by MHC, leading to its low selectivity and low efficiency. In contrast, CAR-T utilizes chimeric antigen receptor technology to genetically modify CD8+ T-cells or bulk T-cells and therefore has no MHC restriction. CAR-T cells exhibit targeted inhibition effects on the immune escape and long-term in vivo survival of tumor cells. Rapoport et al.[18] transfected the NY-ESO-1 antigen-specific TCR gene into autologous T-cells for multiple myeloma treatment. They found that 70% (14 out of 20) patients achieved CR or PR, a 19.1 months mPFS. Furthermore, 75 patients with relapsed and refractory acute lymphoblastic leukemia were treated with anti-CD19 CAR-T cells. It was found that the 6-month event-free survival rate (EFS) and the 6-month OS were 73% and 90%, respectively, while the 12-month EFS and the 12-month OS were 50% and 76%, respectively.[19] Since CAR-T and TCR-T can express synthetic receptor genes and specifically recognize target cells, their treatment applications have been extended to the field of chronic infection and autoimmune diseases.

Security problems

Despite the success of the above cancer immunotherapy strategies in the treatment of malignancies, their safety concerns have limited their clinical applications. Most of the immunotherapy strategies can promote the secretion of cytokines. However, excessive secretion of cytokines can lead to immune-associated pneumonia, increased vascular permeability, tumor metastasis and is often accompanied with risk of secondary infection during treatments.[20] Some patients may also have clinical symptoms such as rash, fatigue, diarrhea, and joint pain. Early intervention and prevention are paramount concerning the above circumstances.[17] In addition, the severe complications of cancer immunotherapy include off-target effect-related toxicity, cytokine storm, and neurotoxicity, of which the underlying pathophysiological mechanisms have not been fully elucidated.[15] Immunotherapy-related adverse reactions are unpredictable and cannot be effectively prevented and treated using Western medicine alone. At present, according to the clinical symptoms of adverse reactions of immunotherapy, TCM attributes them to the syndromes of “upward invasion of fire toxin” or “internal accumulation of dampness and heat.” Therefore, TCM herbs with heat-clearing, detoxicating, or dehumidifying efficacies are empirically used for the prevention and treatment of immunotherapy-related adverse reactions, and the clinical effects are reliable. A combination of TCM and immunotherapy is expected to become an effective and promising strategy for tumor therapy in the near future.


  The Potential Application of Traditional Chinese Medicine in Cancer Immunotherapy Top


TCM is extensively used for cancer treatment in China and Asia with a history of several thousand years. In the Huang Di Nei Jing (《黄帝内经》 Huangdi's Internal Classic), the process of tumorigenesis and metastasis was summarized to be the “Chuan She (传舍)” theory that contained the three elements of (1) cancer toxin, (2) Yang deficiency, and (3) Qi stagnation, blood stasis, and phlegm coagulation. The “Chuan She” theory is consistent with the western “seed and soil” theory in nature. According to the “Chuan She” theory, the occurrence and development of tumors can be attributed to both the exuberance of evil Qi and the deficiency of healthy qi in the metastatic site. They contribute to tumor progression by inducing the formation of stagnant soil and environment. The above process has been summarized thus: “The region where pathogenic factors gather together must be accompanied by healthy qi deficiency” theory.[21] Besides, as stated by the “Chuan She” theory, the disease of a single visceral organ can also affect the function of relevant viscera. Therefore, the prevention and treatment of diseases should be guided by such a holistic view. To achieve this, pretreatment of the undiseased viscera by regulating the Qi function and balance of them is to be done. This will help improve the premetastatic microenvironment and prevent the invasion of cancer toxin, both of which are the main strategies for cancer prevention and treatment in TCM. The above treatment principles have been summarized as the “protecting the unaffected viscera and curing the fundamental pathogenesis first”[22] theory in TCM. A number of clinical and basic studies have suggested that the underlying mechanism of the anticancer effects of TCM lied in the systematic regulation of the host-tumor microenvironment, especially on the immune cells. Given the complex molecular network in the tumor microenvironment, the therapeutic effect of a mono-target intervention strategy is usually very limited; therefore, it precisely brings an opportunity for TCM to demonstrate its therapeutic advantages.

Cytokine regulation

Cytokines play an important role in regulating the type and intensity of the immune response. Modulating the concentrations of cytokines in the tumor immune microenvironment can enhance the anti-tumor immune response. There are many types of cytokines, which can be roughly divided into six categories according to their functions including ILs, IFNs, tumor necrosis factors (TNFs), Colony stimulating factor (CSFs), chemokines (CKs), and growth factors. Accumulating researches have demonstrated that TCM can modulate the secretion of cytokines in multiple ways. (1) IL: Zhao et al.[23] reported that saikosaponin A could increase the levels of serum IL-12 and IFN-γ, whereas it could also decrease the levels of IL-4 and IL-10. Meanwhile, saikosaponin A could promote the differentiation of Th1 cells by increasing the expression of IL-12 receptor and phosphorylated Signal Transducers and Activators of Transcription 4 (STAT4) and therefore it could significantly inhibit the growth and proliferation of breast cancer cells. On the other hand, the IL-6 expression dysbiosis could induce the occurrence and development of tumors. IL-6 could induce the expression of COX-2 by activating signal transducer and activator of transcription 3 (STAT3), upregulating Bcl-xl to resist Fas-L-induced apoptosis.[24] ChungKyung-Sook et al.[25] found that Aster tataricus L. f. could reduce the secretion of IL-1β, IL-6 and TNF-α in the intestine of mice, as well as reduce the expression of inducible nitric oxide synthase and COX-2 protein, exhibiting the chemopreventive effect on colitis-associated cancer in mice. (2) IFN: Ming et al.[26] suggested that tanreqing injection combined with chemotherapy could significantly upregulate the expression of IFN-γ and TNF-α mRNA in Lewis lung cancer tissue of mice and therefore strengthen the killing activity of Cytotoxic T Lymphocyte (CTL) cells and NK cells against the tumor, which finally enhanced the antitumor immune response of mice. Cai et al.[27] reported that trichosanthin could significantly increase the proportion of CD4+ and CD8+ T-lymphocytes, which secreted IFN-γ in tumor-grown mice, thus promoting the Th1 cell-mediated antitumor immune response activity. (3) TNF: TNF-α has the antitumor effect in the early cancer stage. However, it could promote tumor survival and metastasis by stimulating the nuclear factor kappa B (NF-κB)-dependent pathway during tumor progression. TNF-α expressed in tumor cells could promote the formation of paracrine “TNF network” and regulate tumor growth in coordination with IL-6 and CXCL12.[28] Jihye Choi et al.[29] announced that the ethanol extract of Alisma canaliculatum could significantly suppress TNF-α-induced CXCR3 and CXCL10 expression at the gene level, thus inhibiting TNF-α-induced migration of breast cancer cells. (4) CSF: Gilcy K George et al.[30] found that Emilia sonchifolia could significantly downregulate the expression of CSF, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), thus inhibiting the formation of lung metastatic foci and prolonged the survival duration of tumor-bearing mice. (5) CKs: Goranova et al.[31] demonstrated that Tribulus terrestris saponins could inhibit metastasis and induce apoptosis of breast cancer cells by downregulating the gene expression of CXCR4, CCR7, and Bcl-2 in breast cancer cells. Sun et al.[32] demonstrated that bufalin could attenuate the expression of pro-inflammatory mediators including CXCL1, CXCL2, CXCL5, COX-2, TNF-α, IL-1β, and IL-6 and thus suppress the occurrence of inflammation. Further studies indicated that bufalin could exhibit a chemoprevention effect on the inflammation-related colorectal carcinogenesis and antigen-presenting cells (APCs) germline mutation-induced colorectal carcinogenesis in mice. (6) Growth factors (GFs): Moradi-Marjaneh R et al.[33] released their report saying that curcumin could exhibit anti-proliferation, anti-migration, and pro-apoptosis activities in vitro and could modulate miRNAs to inhibit angiogenesis by inhibiting VEGF signal. Transforming growth factor (TGF)-β is the key regulator of epithelial–mesenchymal transformation (EMT) and is closely involved in tumor metastasis.[34] Feng et al.[35] demonstrated that osthol could inhibit TGF-β1-induced EMT, migration, and invasion of lung cancer A549 cells by inactivating the NF-κB pathway. Liu et al.[36] discovered that triptolide could dramatically suppress tumor growth by decreasing the proportion of regulatory T-cells and inhibiting the secretion of TGF-β, VEGF, and IL-10 in tumor-grown mice.

Immune checkpoint regulation

Immune checkpoint inhibitors remain the most mature and widely used immunotherapy strategy at present. Checkpoint molecules, such as CTLA-4 and PD-1/PD-L1, are negative regulators of the immune function of tumor antigen-specific CTLs. Their overexpression could induce the immune escape of tumor cells.[37] Immune checkpoint inhibitors, such as CTLA-4 and PD-1/PD-L1 inhibitors, could relieve the negative regulation of effector T-cells and restore their antitumor immune response by blocking the CTLA-4 or PD-1/PD-L1 signaling. Multiple natural plant drugs could block the inhibitory effect of checkpoint molecules on CTL cells and thus restore and enhance their killing effect on tumors. For example, Jiang et al.[38] proved that ginsenoside Rg3 could significantly attenuate the expression of PD-L1 in human lung adenocarcinoma cell lines A549 and A549/DDP and thus rescue the cytotoxicity of CTL cells. Zhang et al.[39] reported that triptolide could reverse the immune tolerance/inhibition status of CTL cells by inhibiting the expression of PD-1/L1 in glioma cells and thus recover the killing effect of CTL cells on glioma cells. By conducting a prospective randomized controlled clinical trial, Jiang et al.[40] compared the differences of serum sCTLA-4 (soluble CTLA-4) of advanced NSCLC patients between the comprehensive TCM treatment group and the chemotherapy group. It was found that the expression of sCTLA-4 in the comprehensive TCM treatment group was significantly lower than that in the chemotherapy group, which might benefit the survival of advanced NSCLC patients. Xie et al.[41] suggested that the TCM injection of kanglaite could significantly increase the proportions of CD4+ T-lymphocytes in the peripheral blood of patients with advanced breast cancer, and reduce the proportions of CD4+/PD-1+ T-lymphocytes, and therefore reverse the immune suppression effect of the tumor on the human body.

Immune cell regulation

It has been found that when TCM exerts a bidirectional modulation effect on immune cells, it not only positively regulates antitumor effector cells but also negatively modulates the immunosuppressive cells. (1) NK cells: NK cells are the main effector cells involved in antitumor immunity in innate immunity, and the failure of immune clearance against tumor cells by NK cells is a critical mechanism of tumor immune escape.[42] Yu et al.[43] suggested that Ganoderma lucidum polysaccharides could enhance the cytotoxicity of mice NK cells and CTL cells on tumor cells. Luan et al.[44] discovered that ligustrazine could enhance the killing activity of NK cells on tumor cells by inducing NKG2DLs expression and promoting the binding between NKG2D and NKG2DLs. (2) Dendritic cells (DCs): DC cells are the most potent Antigen Prestenting cell (APC) of the immune system. DC cells could initiate the antitumor immune response of effector T-cells, induce specific CTL production, and enhance the cytotoxicity of NK cells. It has been reported that multiple natural herbs could perform an obvious role in promoting the differentiation and maturation of DC cells. Sun et al.[45] suggested that Shengyu decoction could promote the differentiation and maturation of DC cells in the spleen of mice. Meanwhile, Shengyu decoction could also induce the differentiation of T-lymphocytes into CTLs, enhance their lethality, thus improve the antitumor immunity function of mice. Zhang et al.[46] proved that Ganoderma lucidum polysaccharide-loaded gold nanocomposites could effectively induce the activation of DC cells, characterized by increased CD80/CD86/CD40/MHCII expression and elevated phagocytosis efficacy of DC cells. Meanwhile, it also directly stimulated the proliferation of T-cells, thus enhancing the recognition and killing effect of the immune system on cancer cells. (3) Tumor-associated macrophages (TAMs): TAMs could activate the antiapoptotic pathway of tumor cells under a hypoxic microenvironment by modulating inflammatory signal pathways and transcription factors (e.g., NF-κB and STAT3).[47],[48] TAMs could stimulate angiogenesis by secreting VEGF and platelet-derived growth factor.[49],[50] In addition, TAMs-derived metalloproteinases (MMPs) could promote tumor invasion and migration by inducing degradation of the extracellular matrix.[51] Li et al.[52] demonstrated that the polysaccharide extracted from Ilex asprella could regulate TAMs function by modulating TAM polarization. Meanwhile, it could also promote macrophages to secrete cytokines with antitumor activity and induce their antitumor activity through NF-κB and STAT3 pathway. (4) Effector T-cells: Effector T-cells are the “top killer” of the immune cell family that possess a strong killing effect on tumor cells. It has been reported that increased infiltration of effector T-cells predicts better clinical prognosis of cancer patients.[53],[54] Qi et al.[55] reported that yifeitongluo formula could significantly increase the proportion of CD8+ T-lymphocytes, CD4+ T-lymphocytes, and NK cells in the Lewis lung carcinoma mice model and enhance the lethality of these immune cells to tumors, which finally inhibited the growth of tumors and prolonged the OS of tumor-bearing mice. In addition, Th1/Th2 balance plays an important role in the regulation of the antitumor immune response process. Th1/Th2 ratio imbalance, characterized by an increased transformation of Th1 into Th2, usually occurs in blood and tissue samples of cancer patients, and is an important mechanism for tumor immune escape.[56] Ma et al.[57] reported that NSCLC patients who received treatment with a combination of ginseng polysaccharides and DC cells exhibited increased expression of Th1 cytokines (IFN-γ, IL-2) and decreased expression of Th2 cytokines (IL-4, IL-5) when compared with that of DC cells-treated NSCLC patients, suggesting that ginseng polysaccharides could regulate the balance of Th1/Th2, and therefore improve the antitumor immunity activity in NSCLC patients. The potential effects of TCM on immune cell regulations are summarized in [Figure 2].
Figure 1: The process of adoptive T-cell Immunotherapy

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Figure 2: The antitumor immunomodulatory effect of traditional Chinese medicine

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Cytokine storm inhibition

Cytokine storm, also known as cytokine release syndrome (CRS), ranks as the number one obstacle for successful tumor immunotherapy in the clinic. Cytokine storm is an overactivated immune-inflammatory response. It is characterized by excessive release of pro-inflammatory cytokines (e.g., IL-6, IL-8, IL-10, IL-1, TNF-α, and IFN) in a short time, which causes systemic inflammatory reactions. The clinical manifestations include high fever, hepatosplenomegaly, hepatic insufficiency, lymphadenectasis, rash, neurological symptoms, and even respiratory failure and multiple organ failure in severe cases. CRS can greatly increase the permeability of vascular intima, destroy the normal tissues of the human body, and subsequently lead to secondary infection and tumor metastasis. At present, etoposide and inflammatory factor blockers (e.g., anti-IL-6/6R antibody and emapalumab) remain the limited choice for CRS treatment in Western medicine. Although there have been no TCM-related researches focusing on the prevention and treatment of CRS caused by tumor immunotherapy, CRS can be classified into the category of warm-heat disease in TCM according to the clinical symptoms of CRS patients. A plenty of studies have suggested that TCM herbs with heat-clearing, detoxicating, or dehumidifying efficacies may be effective for the prevention and treatment of CRS. For example, Resveratrol is a bioactive substance of many kinds of natural Chinese herbal medicine, including veratrum grandiflorum, polygonum cuspidatum and cassia toraLinn.[58] Rieder et al.[59] demonstrated that resveratrol could significantly reduce vascular permeability and inflammatory response, promote myeloid-derived suppressor cells, and inhibit T-cell activation and thus alleviate CRS. Chen et al.[60] suggested that Xuebijing injection could stimulate the differentiation of Treg cells in vitro, while it could promote the amplification of IL-10+ Treg cells in mice sepsis model in vivo. Meanwhile, Xuebijing injection could significantly reduce the levels of serum TNF-α and IL-6, improving the survival rate of septic shock mice. These results indicated that Xuebijing injection may be useful for CRS prevention and treatment. In addition, a single-center, double-blind, randomized controlled trial demonstrated that Xuebijing injection could attenuate IL-1β, IL-8, and C-reactive protein expression, but increase IL-10 expression, thus protecting the lungs of patients.[61]


  Outlook Top


TCM is the quintessence of the medicine in China. In recent years, the Chinese government strongly encourages and supports the development of TCM. By the above reviewing of the research progress of TCM in cancer treatment field, it can be concluded that growing efforts are being made by TCM clinicians and researchers to prevent and treat cancer by regulating the immune function of tumor patients. The immune function of the human body gradually declines along with the occurrence and progression of tumors, especially tumors in their advanced stage. Both the innate immunity function and the specific immunity function of the cancer patients are significantly suppressed. Accumulating studies have demonstrated that TCM not only enhances the immune function of the human body but also enhances the sensitivity of tumor patients to radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, there are still some obstacles to surmount for successful cancer immunotherapy by TCM. The main problems are as follows: (1) the antitumor efficacies of TCM drugs are mainly based on experience inheritance or personal long-term application experience, whereas there is a lack of high-quality randomized controlled clinical trials to verify them; (2) it is difficult to control the quality of TCM drugs because of the complexity in wide dosage range and multiple sources of TCM drugs; (3) lack of standardization in the syndrome differentiation and curative efficiency evaluation, as well as the lack of a reliable system for safety evaluation; and (4) the complicated and unclear action mechanisms of TCM drugs. To solve the above shortcomings, the standardization of TCM research is of urgent need and has obtained enormous support from the China government. We are confident that TCM will play more and more important roles in the tumor immunotherapy field in the near future.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (82074165, 81873306, 81973526, 81703749, 81703764); Guangdong Science and Technology Department (2016A030306025); Guangdong High-level Personnel of Special Support Program (A1-3002-16-111-003); Department of Education of Guangdong Province (2018KZDXM022, A1-2606-19-111-009); the Ph.D. Start-up Fund of Natural Science Foundation of Guangdong Province (2017A030310213); Science and Technology Planning Project of Guangdong Province (2017B030314166); Guangzhou science and technology project (201904010407); the Specific Research Fund for TCM Science and Technology of Guangdong provincial Hospital of Chinese Medicine (YN2018MJ07); and the Foundation for Young Scholars of Guangzhou University of Chinese Medicine (QNYC20190101).

Conflicts of interest

There are no conflicts of interest.



 
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