Xiaopei Hao1†
Guangshun Sun2†
Yao Zhang1†Xiangyi Kong1Dawei Rong1Jinhua Song1*
Weiwei Tang1*Xuehao Wang1*- 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
- 2Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.
Introduction
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for the sixth most common type of cancer and the second leading cause of death among all cancers (Ferlay et al., 2015). Due to changes in environmental factors, immunization and people’s lifestyle, the incidence of HCC and HCC-related mortality are increasing all over the world. The latest research indicates that HCC accounts for approximately 85% of patients diagnosed with liver cirrhosis. Its 5-year survival rate is only 18%, second only to pancreatic cancer (Asafo-Agyei and Samant, 2021). With the improvement of the treatment level for HCC, a variety of treatment options such as liver transplantation, surgical removal, systemic therapy and liver targeted therapy are constantly enhanced and created. At present, only surgical treatment is considered as a potential radical treatment for HCC. But only 15% of HCC patients have the opportunity to have surgery, most patients are found in the advanced stage (Roxburgh and Evans, 2008). Sorafenib is the only systemic medication approved by the FDA for advanced HCC. However, because of the overexpression of dihydropyrimine dehydrogenase, the multi-drug resistance gene MDR-1and p-glycoprotein gene products, HCC is regarded a chemotherapy-resistant tumour, and how to execute effective chemotherapy is still a major difficulty (Soini et al., 1996; Jiang et al., 1997; Kato et al., 2001).
Seven essential characteristics of cancer have been identified as crosstalk between cells and immune cells, self-sufficiency of signals for growth, unrestricted replication potential, apoptosis avoidance, growth signals insensitivity and continuous angiogenesis and invasion/metastasis of tissue (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). Tumor cells, immune cells, stromal cells, endothelial cells, and cancer-related fibroblasts are all found in the tumour microenvironment (TME), according to current research. Malignant tumour cells can evade immune monitoring and kill, as well as impair the human body, via a range of intricate ways (Hanahan and Weinberg, 2011). Due to the limitations of traditional chemotherapy regimens in the treatment of HCC, a variety of immunotherapy methods for HCC have been developed. Immunotherapy mostly employs immune cells within or outside of the TME to specifically target and assault cancer cells, with the benefits of high specificity and low side effects (Yost et al., 2019). More crucially, thanks to advances in tools such as mass spectrometry and single-cell RNA sequencing, We can map immunological cells in TMEs at the single-cell level (Spitzer and Nolan, 2016; Zheng et al., 2017; Papalexi and Satija, 2018; Wang et al., 2019a). We outline the significance of tumor-associated immune cells in the HCC tumour microenvironment and highlight their relevance in HCC cancer immunotherapy in this study.
The Immune Cells in TME
Tumor-associated immune cells are broadly classified into two types: tumor-promoting immune cells and tumor-antagonistic immune cells. At different stages of tumour formation, these two types of cells play different functions and impact each other (Figure 1). Because the significance of tumor-associated B cells in tumour growth is debatable, we shall introduce B cells additionally.
FIGURE 1. A schematic overview of the most important mechanisms and interactions of the tumor microenvironment. Tumor cells interact with other cells in various ways. CSC indicates cancer stem cell, ECM indicates extracellular matrix, CTL indicates cytotoxic T lymphocytes.
Tumor-Antagonizing Immune Cells
Effector T Cells
Current studies suggest that CD8+ cytotoxic T cells (CTLs) are the main lymphocytes that kill cancer cells. When CD8+ T cells recognize antibodies on DC, CD80−CD86 and CD70 ligands on DC connect to CD27 and CD28 receptors on CD8+ T cells, and CD8+ T cells are modified to become cytotoxic effector CD8+ T cells (Tanaka et al., 1999; Farhood et al., 2019). Furthermore, CD4+ T cells can activate CD8+ T cells through CD40−CD40L interaction, and CD4+ T cells can produce IL-2 to enhance CD8+ T cell proliferation. CD4+ T cells are also important in the maturation of CD8+ T cells into memory cells (Bennett et al., 1997; Mackey et al., 1997; Bennett et al., 1998; Mackey et al., 1998; Schoenberger et al., 1998; Bourgeois et al., 2002; Cheng et al., 2002; Borst et al., 2018). CTL kills target cells through granular exocytosis and apoptotic induction mediated by FasL ligand (FasL) in working state. CTL can also produce interferon- (IFN-) and tumour necrosis factor (TNF-) to cause cancer cell cytotoxicity (Farhood et al., 2019). Activation and regulation of CTL requires signals from T cell receptors (TCR) and immune checkpoints (Rogler et al., 1999). For example, cancer cells inhibit CTL activity through the expression of a ligand that binds to an inhibitory checkpoint, such as PD-L1 (Iwai et al., 2002). A significant number of studies have established the function of CD8+ T cells and CD4+ T cells in the formation and progression of HCC, including diagnosis/treatment/prognosis, and so on.
Chang et al. 's study confirmed that NanoMnSor improves the effectiveness of anti-PD-1 antibodies and whole-cell cancer vaccine immunotherapy by encouraging macrophage polarization to an immunostimulating M1 phenotype, decreasing hypoxica-induced tumor infiltration of tumor-associated macrophages, and raising the number of CD8 cytotoxic T cells in tumors, thereby reprogramming immunosuppressive TME (Chang et al., 2020). Xie et al. 's research proposed that PD-L1 overexpression is mostly triggered by pre-existing activated CD8 (+) cytotoxic T cells in the HCC environment, rather than being produced constitutively by tumor cells, and that it is a good prognostic factor for HCC (Xie et al., 2016). The frequency of circulating PD-1 (+) CD8 (+) T cells increases as the illness develops from LC to HCC. PD-1 expression was shown to be much higher in tumor-infiltrating CD8 (+) T cells. In vitro, CD8 (+) T cells promoted the production of PD-L1 on HCC cells in an IFN-dependent way, increasing CD8 (+) T cell death, whereas inhibiting PD-L1 reversed this effect (Shi et al., 2011).
Both in vitro restimulation and in vivo depletion studies have indicated that CD4+ and CD8+ lymphocytes contribute to anticancer activity. ASPH activation resulted in considerable production of antigen-specific CD4+ T cells in PBMC from healthy volunteers and HCC patients (Shimoda et al., 2012). Lack of recovered CD19+, CD3+, CD4+, and especially CD8+ T cells is associated with poor survival in patients (Carr and Metes, 2012). Zhou et al. ‘s revealed that antibodies against CD274 (PD-L1), LAG3, or TIM3 boost CD4+ and CD8+ TIL proliferation and cytokine secretion in response to polyclonal antigens or TAA stimulation (Zhou et al., 2017). More research results on the effect of Effector T cells in HCC are summarized in Table 1. It is clear that Effector T cells play a critical role in the immunological milieu of HCC. Many studies have shown that targeting these cells is effective in patients with HCC.
TABLE 1. The immune cells in TME: Effector T cells.
NK Cells
NK cells are an essential anti-tumor immune cell that primarily mediates immune surveillance of malignancies. It performs a similar function as CD8+ T cells: NK cells regulate the killing response of tumor cells by releasing perforin and granulein, triggering apoptosis in target cells. In addition, to improve their anticancer activity, NK cells can produce proinflammatory cytokines and chemokines (Voskoboinik et al., 2006; Guillerey et al., 2016; Habif et al., 2019). Existing studies have confirmed the value of NK cells in the development, targeted therapy, prognosis of HCC. Sprinzl et al. 's research confirmed that Sorafenib can promote the pro-inflammatory response of tumor-associated macrophages in HCC, and then activate the anti-tumor NK cell response through the cytokine and NF-κB pathway (Sprinzl et al., 2013). Senescence monitoring necessitates the recruitment and maturation of CCR2 myeloid cells, and CCR2 deficiency promotes HCC growth. Conversely, HCC cells suppress the maturation of recruited myeloid progenitors, which promotes mice HCC growth and worsens prognosis and survival in human HCC patients via NK cell inhibition (Eggert et al., 2016). Kohga et al. 's revealed that natural killer (NK) cells had stronger cytolytic activity on ADAM9KD-HCC cells than on control cells, and that this cytotoxicity is enhanced by the MICA/B and NK group 2, D pathways. Sorafenib treatment resulted in a decrease in ADAM9 expression in HCC cells, an increase in membrane-bound MICA expression, and a decrease in the quantity of soluble MICA. Sorafenib increased HCC cell NK sensitivity by boosting the expression of membrane-bound MICA (Kohga et al., 2010a). Table 2 summarizes current research on NK cells in HCC, confirming the importance of NK cells in immune escape and anti-HCC therapy.
TABLE 2. The immune cells in TME: NK cells.
Dendritic cells
DC cells, as specialized antigen-presenting cells in the human body, can present antigens to T cells and produce costimulatory signals for T cell activation. According to the current study, mature DC cells can penetrate tumor cells and limit tumor incidence and progression. Under many severe conditions, this inhibition effect will be avoided by tumors through certain means. Therefore, targeting at DC cells, some studies have reported its role in the occurrence, development, immunotherapy, diagnosis and prognosis of HCC. For example, In mice, combining DC vaccination and PD-L1 inhibitor treatment can result in longer overall life, reduced tumor volume, and increased tumor cell apoptosis. As a new therapy method for HCC, combined treatment with DC vaccination and PD-L1 inhibitor may offer promising results (Teng et al., 2020). Ali et al. 's research clarified that the combination of PEI or RFTA with active antigen-specific immunotherapy using DCS is a promising approach to induce a sustained anti-tumor immune response aimed at reducing tumor recurrence and metastasis in patients with HCC. Table 3 summarizes the current role of DC cells in HCC.
TABLE 3. The immune cells in TME: Dendritic cells.
M1-Polarized Macrophages
Another important type of immune cell in TME is macrophages derived from circulating monocytes, which can generally be divided into M2 polarization and M1 polarization (Figure 2). M1-polarized macrophages, for example, can create pro-inflammatory cytokines and reactive oxygen species/nitrogen to prevent the formation and progression of malignancies (Aras and Zaidi, 2017). There are limited investigations on the function of M1-polarized macrophages in HCC at the moment. Studies have shown that M1-polarized macrophages in the S3 subclass in HCC increased, and the prognosis was good. Memory B cells, Total B cells, M1 macrophages and T follicle helper cells, were linked with strong total immune cell infiltration into HCC, whereas resting mast cells, neutrophils, and NK cells were associated with poor infiltration (Rohr-Udilova et al., 2018). Table 4 summarizes the current role of M1-polarized macrophages in HCC.
FIGURE 2. M1/M2 model of macrophage activation. M1 cells exert an inflammatory phenotype and are involved in killing bacteria, viruses and tumor cells, while M2 cells are involved in killing encapsulated parasites, immunosuppression, angiogenesis, etc.
TABLE 4. The immune cells in TME: M1-polarized macrophages.
Tumor-Promoting Immune Cells
In the immune microenvironment of HCC, some cells could promote the occurrence and development of HCC, and we will review them one by one.
Regulatory T cells(Tregs)
Tregs play a vital role in immunological homeostasis and immune self-tolerance, and they can express the CD4+ marker and the Foxp3 marker (Samstein et al., 2012). Foxp3+ Treg acts as a switch for all levels of immune response, and its effects appear to be two-sided. First, Treg can inhibit harmful immune responses and thus inhibit the occurrence of autoimmune diseases (Berod et al., 2012). Second, Treg suppresses protective immune responses against invading pathogens or tumors, leading to further progression of the disease (Sakaguchi et al., 2010). How does Treg play a role in tumors, including how does Treg infiltrate and metastasize to tumor sites or how does Treg help tumors evade immune monitoring, has become a hot research topic in recent years. Many ideas have been put forward. Tregs were found in much higher numbers in HCC patients than in healthy controls. In addition, patients with high Treg(III) levels after TACE had a significantly lower progression-free survival than patients with low Treg(III) levels after TACE (Park et al., 2020). Other studies have shown that tumor Treg upregulated the expression of the glucocorticoid-induced tumor necrosis factor receptor (GITR). Treatment with soluble GITR ligand (GITRL) reduced inhibition caused by activated tumor infiltrating Treg and restored CD4+ CD25-T cell proliferation and cytokine production. (Pedroza-Gonzalez et al., 2013). In addition to that, the proportion of Tregs cells in HCC patients was significantly higher than that in healthy and cirrhosis controls, and was related to various clinical indicators of HCC patients. In HCC patients with BCLC stage C, the proportion of Treg cells was more pronounced than in BCLC stage B patients. One to 2 weeks after surgery, the fraction of Treg cells was much lower than before GSMS-TACE. Three to 5 weeks following surgery, the proportion of Treg cells continued to decline (Ren et al., 2021). Table 5 summarizes the most credible studies related to the role of Treg in HCC.
TABLE 5. Tumor-promoting immune cells: Regulatory T cells.
Myeloid-Derived Suppressor cells
MDSC is thought to be a cancer-promoting immune cell in the HCC tumor microenvironment and was discovered a decade ago (Gabrilovich et al., 2007). MDSC is divided into granulocyte or multinuclear MDSC(PMN MDSC) and mononuclear MDSC(M-MDSC) (Veglia et al., 2018). MDSCs enhance angiogenesis by producing vascular endothelial growth factor (VEGF), actuator 2 and MMP9. They can also cause cancer cells to migrate to endothelial cells and encourage metastasis (Zhou et al., 2018a). MDSC also suppresses T cell activity by secreting immunosuppressive cytokines, inducible nitric oxide synthase, and argininase (Gabrilovich et al., 2012; Gabrilovich, 2017). MDSCs can have a dual influence on immune cells via distinct methods. B cells, T cells, DCs and NK cells, are all inhibited by MDSCs. MDSCs, on the other hand, can stimulate Th17 cells, Tregs, and TAMs, as well as tumor angiogenesis and metastasis (Figure 3). There has been a great deal of research on the processes through which MDSC supports the advancement of HCC, and many therapeutic pathways have been developed for MDSC as a target of HCC. For example, myeloid-derived suppressor cells (MDSCs) are drawn to the tumor microenvironment by PIWIL1-overexpressed HCC cells. MDSCs consumption reduced the proliferation and growth of PIWIL1-overexpressed HCC tumors. Complement C3 stimulates HCC cell secretion via PIWIL1 and mediates the contact between HCC cells and MDSC via p38 MAPK activation in MD38, and then initiates the expression of immunosuppressive cytokine IL10. PIWIL1, which is expressed by tumor cells, could be a viable target for the development of new HCC treatments (Wang et al., 2021a). Tumor-infiltrating LY6G MDSCs from orthotopic liver tumors treated with sorafenib dramatically increased CD4 T cells expressing IL-10 and TGF-and decreased CD8 T cell cytotoxicity. In vitro, IL-6 protects LY6G MDSC from sorafenib-induced cell death. Combining sorafenib and anti-IL-6 antibody or anti-LY6G antibody dramatically decreased the cell proportion of LY6G MDSCs in orthotopic liver tumors, synergistically boosted sorafenib’s therapeutic efficacy and increased T cell proliferation (Chang et al., 2018). Icaritin blocks MDSC production by blocking the attenuation of EMH, thereby inhibiting the immunosuppressive effect of the tumor, thereby triggering an anti-tumor immune response. Therefore, Icaritin can be used as a new adjuvant or even as an independent therapeutic agent for the effective treatment of HCC(Tao et al., 2021). In Table 6, we show the relevant role of MDSC in HCC immune microenvironment in recent years.
FIGURE 3. The mechanism of MDSC-mediated immunosuppression. MDSC inhibits the functions of DC, T cells, B cells and NK cells by secreting various cytokines, while promoting the functions of Th17, Treg, TAMs cells, and can promote angiogenesis and metastasis.
TABLE 6. Tumor-promoting immune cells: Myeloid-derived suppressor cells.
Cancer-Associated fibroblasts
CAF is not an immune cell, but it plays an important role in the tumor microenvironment, so we will introduce it in detail here. CAF exists as a prominent component of the tumor stroma between various inflammatory cells and components in the tumor microenvironment (Kalluri, 2016). As a result, CAF possesses functions that normal fibroblasts do not. A vast number of prior studies have demonstrated that CAF plays a critical function in changing the tumor microenvironment and driving the development of a variety of cancers (Jiang et al., 2017a; Zhao et al., 2017a; Deng et al., 2017; Pistore et al., 2017). CAF is also significant in HCC. Many studies have revealed the great role of CAF in the pathogenesis, progression, prognosis, treatment and other aspects of HCC. CAF-derived cardioctonutrient-like cytokine 1 (CLCF1) has been found in studies to stimulate the release of TGF-β and CXCL6 in tumor cells, consequently increasing tumor stem cell development in HCC-TME (Song et al., 2021). Other research have found that CCN2, EMA, and FAP expression may be involved in the activation of CAF in HCC, resulting in aggressive behavior. The substantial association between EMA-expressing tumor cells and FAP-expressing CAF, as well as their topographical proximity, suggests that there may be interplay between tumor epithelial and stromal cells in the HCC tumor microenvironment (Kim et al., 2014). Table 7 summarizes the current role of CAF in HCC.
TABLE 7. Tumor-promoting immune cells: cancer-associated fibroblasts.
M2-Polarized Macrophages
M2 polarized macrophages, as opposed to M1 polarized macrophages, have anti-inflammatory and pro-tumor actions (Figure 4). M2 macrophages are further differentiated into M2a, M2b, M2c, and M2d subsets. Th2 cytokines such as IL-13 and IL-4 can trigger macrophage transformation to the M2A phenotype, whereas TLR and immune complex activation induces M2B macrophages, the M2C subtype polarized by IL-10 (Hao et al., 2012; Sica and Mantovani, 2012). Despite the fact that there have been few research on M2-polarized macrophages in HCC, the function of them in the occurrence and development of HCC has been confirmed. According to several studies, arsenite raises miR-15b levels and causes M2 polarization in THP-1 cells. Increased miR-15b in Evs transfer from arsenite-treated THP-1 (AS-THP-1) cells to HCC cells via miR-15b. By targeting LATS1, it can reduce Hippo pathway activation while still accelerating the invasion and metastasis of growing HCC cells (Li et al., 2021). The potential therapeutic potential of M2 polarized macrophages has also been pointed out that Tumor cell-derived Wnt ligands induce M2-like polarization of TAM via traditional Wnt/-catenin signaling, resulting in tumor migration, development, immunosuppression and metastasis in HCC(Yang et al., 2018a). We summarize the current relevant research progress in Table 8.
FIGURE 4. The different ways that TAM supports tumor growth. TAM promotes tumor proliferation, invasion, angiogenesis, and immune escape through various methods.
TABLE 8. Tumor-promoting immune cells: M2-polarized macrophages.
The Controversial Immune Cell Type in Cancer: B Cells
One type of immune cells that cannot be ignored in the HCC tumor microenvironment is B cells. According to the current relevant studies, it is not clear whether B cells are “good” or “bad”. Some studies have reported that B cells promote HCC, while others have reported the opposite effect. B cells, on the one hand, release cytokines that comport with CTL activity and serve as potent antigen-presenting cells (APCs). On the other hand, they may be tumorigenic due to the production of cytokines that attract MDSC and promote angiogenesis (de Visser et al., 2005; Tsou et al., 2016). Studies have shown that CCL20 derived from tumor cells interacts with CD19CD5 B cells overexpressed by CCR6 to promote the development of HCC, possibly through enhanced angiogenesis (He et al., 2017). Liu et al. 's study confirmed that Selective recruitment of CXCR3 (+) B cells Bridges the pro-inflammatory interleukin-17 response and the polarization of tumorigenic macrophages in the tumor environment, and blocking the migration or function of CXCR3+ B cells may help to overcome HCC (Liu et al., 2015). Therefore, B cells are involved in both the development and inhibition of HCC. Table 9 highlights the most recent reliable research on the involvement of B cells in HCC.
TABLE 9. The controversial immune cell type in cancer: B cells.
Conclusions and Perspectives
With the development of single-cell sequencing and other technologies, we have the opportunity to further explore TME. Immunotherapy, a new tumor treatment method, also has a better and broader application prospect. However, at present, it is still too early for immunotherapy to replace traditional chemotherapeutic therapy, and there is still a long way to go in the process of clinical application. However, immunotherapy can be regarded as a good alternative therapy for patients with chemotherapy resistance. As mentioned in this paper, immunotherapies for tumor suppressor related immune cells, such as effect DCs, as well as tumor promoting immune cells, such as MDSC/Treg, are being developed one after another.
Compared with traditional chemotherapy, immunotherapy has many advantages. For example, immunotherapy has fewer overall side effects than chemotherapy and, once effective, may lead to long-term survival and even clinical cure. In addition, immunotherapy can be used as an important anti-tumor adjuvant therapy in addition to chemotherapy, radiotherapy and surgery. Appropriate immunotherapy can kill the tiny residual tumor cells after chemotherapy or some tumor cells resistant to chemotherapy. Immunotherapy should be considered for patients who are intolerant to chemotherapy or have extensive metastasis and cannot undergo surgery, radiotherapy or chemotherapy (Yang, 2015).
At present, the mainstream immunotherapy mainly includes CAR T therapy/immune checkpoint inhibitor therapy (PD-1, PD-L1, etc.)/tumor vaccine. CAR-T is the T cells, biological engineering, when the cancer has an immune deficiency, immune surveillance, give play to the role of the case, through the biological engineering to determine the targets of leukemia, it specifically chimeric in T cells, to attack the leukemia cells, the effect is significant, but easy to appear “storm” cells, serious and even cause death (Feins et al., 2019). Immune checkpoint inhibitor therapy has the advantage of long-term survival and relatively small adverse reactions. This therapy activates tumor-specific immune cells in the body by removing or attenuating the negative regulatory factors of immunoreactive cells, but it is not suitable for all patients. The higher the mutation load, the better the treatment response. Therefore, biomarkers should be used to screen the dominant population. The most common predictive indicators of PD-1/PD-L1 immune checkpoint inhibitors are microsatellite instability, PD-L1 and tumor mutation load (Pinato et al., 2019). The treatment of cancer vaccines is still incomplete.
Immunotherapy is not the end of tumor therapy; on the contrary, tumor immunotherapy represented by immune checkpoints has just opened a new chapter in tumor therapy. Combined with the basic and characteristics of immunotherapy, with the deepening of human understanding of tumors, tumors as a chronic disease that can be cured are no longer so far out of reach.
Author Contributions
The manuscript had three first authors who made equal contributions to the project. XH, GS, and YZ were responsible for collecting information and design reviews of relevant studies. XK and DR are responsible for drawing the pictures. In addition, we have three corresponding authors in this manuscript. WT, JS, and XW contributed to the interpretation, editing and critical revision of the manuscript.
Funding
We are grateful for the grants from the National Natural Science Key Foundation of China (Grant No. 31930020) and National Natural Science Foundation of China (Grant No. 81771716).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Acknowledgments
We would like to express our sincere thanks to Magdalens Klink, the author of the book “Interaction of immune and cancer cells.” Our pictures have been partially changed and repainted on the basis of this book. At the same time, this book has also given us a lot of writing inspiration.
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Keywords: HCC, TAM, NK cell, cancer immunotherapy, challenge, development
Citation: Hao X, Sun G, Zhang Y, Kong X, Rong D, Song J, Tang W and Wang X (2021) Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front. Cell Dev. Biol. 9:775462. doi: 10.3389/fcell.2021.775462
Received: 14 September 2021; Accepted: 19 October 2021;
Published: 12 November 2021.
Edited by:
Dechun Feng, National Institute on Alcohol Abuse and Alcoholism (NIAAA), United StatesReviewed by:
Talib Hassan Ali, University of ThiQar, IraqSaisha Nalawade, Baylor College of Medicine, United States
Copyright © 2021 Hao, Sun, Zhang, Kong, Rong, Song, Tang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xuehao Wang, wangxh@njmu.edu.cn; Weiwei Tang, 1243773473twww@sina.com; Jinhua Song, jinhuasongnanj@163.com
†These authors share first authorship