DOI:10.1101/gad.314617.118.png

摘要

How do cancer cells avoid the destruction by immune attack?

In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells.
however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack.

注：

1. Immune tolerance
   Immune tolerance is the state of unresponsiveness of the immune system to substances or tissues that have the potential to induce an immune response. Self tolerance to an individual's own antigens is achieved through both central tolerance and peripheral tolerance mechanisms.（来源：https://www.nature.com/subjects/immune-tolerance）

Central tolerance encompasses the mechanisms that render newly developing lymphocytes in primary lymphoid organs tolerant to self antigens. Developing B cells and T cells that react strongly to self antigens either undergo alteration of their antigen receptors, or face functional inactivation, deletion by apoptosis or programming into a suppressive phenotype.(https://www.nature.com/subjects/central-tolerance)
Peripheral tolerance describes the mechanisms that take place outside of primary lymphoid tissues to prevent lymphocytes from initiating potentially dangerous immune responses against the body’s own tissues, or against other harmless materials, such as food or commensal organisms.(https://www.nature.com/subjects/peripheral-tolerance)

在生理条件下，机体免疫系统对外来抗原产生免疫应答以清除病原体，对体内组织细胞表达的自身抗原，却表现为“免疫不应答”，避免引起自身免疫病。 这种抗原特异性 T、B 细胞，在抗原刺激下，不能激活产生特异免疫效应细胞， 从而不能执行免疫应答的现象，称为免疫耐受(immunological tolerance)。免疫耐受具有免疫特异性，即只对特定的抗原不应答，对不引起耐受的抗原，仍能进行良好的免疫应答。这不同于免疫缺陷或免疫抑制药物引起的对免疫系统的普遍抑制作用。免疫耐受的作用与免疫应答相反，但两者均是免疫系统的重要功能组成，对自身抗原的耐受， 避免发生自身免疫病;与此同时，免疫系统对外来抗原或内源新生抗原应答，执行抗感染、抗肿瘤的防卫功能，显示为免疫应答与免疫耐受的平衡，保持免疫系统的自身(内环境)稳定。(https://qinqianshan.com/biology/immunobiology/immunological-tolerance/)
免疫耐受按其形成时期的不同，分为中枢耐受及外周耐受。中枢耐受(central tolerance)是指在胚胎期及出生后 T、B 细胞发育过程中，遇自身抗原所形成的耐受;外周耐受(peripheral tolerance)是指成熟 T、B 细胞，遇内源性或外源性抗原所形成的耐受。两类耐受诱因及形成机制有所不同。(https://qinqianshan.com/biology/immunobiology/immunological-tolerance/)
外周免疫耐受机制：诱导外周免疫耐受的抗原主要是组织特异性自身抗原。该种自身抗原多数在骨髓和胸腺中不表达，因此识别此类自身抗原的自身反应性 T、B 淋巴细胞可以进入外周免疫器官，并通过以下作用机制对组织特异性自身抗原产生免疫耐受。(https://qinqianshan.com/biology/immunobiology/immunological-tolerance/)

2. Lymphoid Organs: Primary and Secondary（https://www.biologydiscussion.com/immunology/lymphoid-organs-primary-and-secondary-with-diagram/56268）
   
   https://www.biologydiscussion.com/immunology/lymphoid-organs-primary-and-secondary-with-diagram/56268.png
   
   Primary Lymphoid Organs:
   In primary lymphoid organs, immature lymphocytes differentiate to mature ones into an antigen sensitive lymphocytes and after maturation, lymphocytes migrate to secondary lymphoid organs.
   These are of two types:

(a) Bone marrow
It is the main lymphoid organ, where all the lymphocytes and all the body cells are produced and T-lymphocytes are developed.
(b) Thymus
It is a lobed organ, located near the heart and beneath the breast bone. It is large at the time of birth but with age, the size keep on reducing and becomes very small by attaining puberty. Growth and maturation of T-lymphocytes takes place in thymus only.
note:
Both bone marrow and thymus provide micro-environments for the development and maturation of T-lymphocytes.

Secondary Lymphoid Organs:
These organs provide the sites for the interaction of lymphocytes with the antigen, which then proliferate to become effector cells.
These are of following types:

(a) Spleen
It is a large bean-shaped organ containing lymphocytes and phagocytes. It filters the blood by trapping the pathogens in it.
(b) Lymph nodes
These are small solid structures located at different points along the lymphatic system. Their function is to trap the microorganisms or other antigens, that enter the lymph and tissue fluid. Therefore, the antigens trapped in the lymph nodes are responsible for the activation of lymphocytes present there and cause the immune response.
(c) Mucosal associated Lymphoid Tissue (MALT)
This is located within the lining of main tracts in the body like respiratory, digestive, urogenital tracts. MALT constitutes about 50% of the lymphoid tissue in human body.

背景

• Primary and metastatic tumors are complex ecosystems composed of neoplastic cells, extracellular matrix (ECM), and “accessory” nonneoplastic cells, which include resident mesenchymal support cells, endothelial cells, and infiltrated inflammatory immune cells. Cross-talk between cancer cells and accessory cells fuels and shapes tumor development. During tumor formation, the tissue architecture evolves into a highly specialized microenvironment characterized by a corrupted ECM and chronic inflammation.
• Cancer-associated inflammation, which is present at different stages of tumorigenesis, contributes to genomic instability, epigenetic modification, induction of cancer cell proliferation, enhancement of cancer anti-apoptotic pathways, stimulation of angiogenesis, and, eventually, cancer dissemination.
• Studies during the last two decades have demonstrated that inflammatory immune cells are essential players of cancer-related inflammation. Efforts have focused on understanding how immune cells impact tumor fate in different stages of disease: early neoplastic transformation, clinically detected tumors, metastatic dissemination, and therapeutic intervention.

Cancer-related inflammatory conditions

• Today, it is accepted that chronic inflammation is a critical hallmark of cancer, with at least 25% of cancers associated with it (Hussain et al. 2000; Coussens and Werb 2002; Beaugerie et al. 2013), and possible underlying causes include microbial infections, autoimmunity, and immune deregulation.
  For example, human papilloma viruses (HPVs) induce inflammation and are responsible for 90%–100% of all cervical cancers (Bosch et al. 2002).

p1.png

Chronic inflammation is a necessary consequence of cancer progression. Different inflammatory conditions can lead to neoplastic transformation. However, whether or not the inflammation is present in the origin of carcinogenesis, most tumors progress to a state of chronic inflammation that fuels different aspects of tumor progression, including genomic and epigenomic instability, immune evasion, angiogenesis, and metastatic dissemination.

While chronic inflammation has an important role in cancer, less is known about the impact of acute inflammation on tumor progression.

• For example, inducing acute inflammation locally in the bladder with a vaccine containing an attenuated Mycobacterium bovis strain successfully treats squamous cancer of the bladder (Askeland et al. 2012).
• Hence, with the infiltration of leukocytes and subsequent inflammation, the impact from inflammatory mediators can both initiate and, in certain cases, eliminate tumor cells and prevent tumor development (Shalapour and Karin 2015).
• This dual role of inflammation also becomes evident in the clinic, where immunodeficient patients are more often diagnosed with cancer(Frisch et al. 2001).
• Interestingly, long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), which suppresses the immune system, has been linked to a lower risk of cancer (Thun et al. 2002).

思考：第三条研究结果与第四条研究结果为什么看起来那么矛盾？免疫被抑制到底是好事还是坏事？

• Whether or not inflammation is a cause or a consequence, the tumor microenvironment (TME) is compromised, triggering an immune inflammatory response, and histopathological analyses provide evidence for the presence of innate and adaptive immune cells in most human tumors, which are characterized as features of cancer progression (Fridman et al. 2012).

Role of inflammatory cells during cancer progression

How do cancer cells avoid destruction by the immune system?

• It is currently accepted that an aberrant innate and adaptive immune response contributes to tumorigenesis by selecting aggressive clones, inducing immunosuppression, and stimulating cancer cell proliferation and metastasis(Palucka and Coussens 2016). #这篇文章也很重要，后面再分享

上面这段话值得深思，how, and why

• During the early stages of tumor development, cytotoxic immune cells such as natural killer (NK) and CD8+ T cells recognize and eliminate the more immunogenic cancer cells (Teng et al. 2015).
  This first phase of elimination selects the proliferation of cancer cell variants that are less immunogenic and therefore invisible to immune detection.

癌症早期，毒性细胞会杀死抗原性强的癌症细胞，这也间接地导致留下来的都是抗原性不强的肿瘤细胞（相当于发挥了选择性作用，适者生存）

• As the neoplastic tissue evolves to a clinically detectable tumor, different subsets of inflammatory cells impact tumor fate.
  For example, high levels of tumor-infiltrated T cells correlate with good prognosis in many solid cancers(Clemente et al. 1996; Oldford et al. 2006; Dieu-Nosjean et al. 2008);
  on the other hand, high levels of macrophage infiltration correlate with a worse prognosis (Zhang et al. 2012; Mantovani et al. 2017; Gonzalez et al. 2018).

重点：不同的炎症细胞亚群决定这肿瘤的命运。这里列举了Tcell与巨噬细胞跟生存预后的关系。

p2.png

上面这个图很重要，很有意义

Macrophages（两个亚群，促肿瘤与抑肿瘤）

• Macrophages are innate immune cells that differentiate from circulating classical monocytes after extravasation into tissues.
• Upon differentiation, macrophages are equipped to sense and respond to infections and tissue injuries, playing a key role in tissue homeostasis and repair.
• As crucial drivers of chronic cancer-associated inflammation, their involvement has been described in every step of cancer progression, from early neoplastic transformation throughout metastatic progression to therapy resistance.#巨噬细胞是与癌症相关的慢性炎症的关键驱动因素，参与到整个癌症发展过程中
• In oncological patients and preclinical experimental models, high-grade tumor-associated macrophages (TAMs) correlate with poor prognosis and reduced overall survival (Zhang et al. 2012; Noy and Pollard 2014).

图片.png

• Activated macrophages are referred to as either proinflammatory (“M1 type,” driven by LPS and IFNγ) or anti-inflammatory (“M2-type,” driven by IL-4 or IL-13)(Mantovani et al. 2002).
• During carcinogenesis, anti-tumor macrophages display an M1-like polarization that plays a relevant role in the elimination of more immunogenic cancer cells. As the tumor progresses, the TME elicits an M2-like polarization of TAMs that is protumorigenic (Mantovani et al. 2017).
• TAMs promote tumor progression in different ways, such as stimulating angiogenesis and lymphangiogenesis, stimulating both cancer cell proliferation and epithelial–mesenchymal transition, limiting the efficacy of therapies, remodeling the ECM, promoting metastasis, and inducing immunosuppression of anti-tumor effector immune cells (DeNardo et al. 2011; Qian et al. 2015; Mantovani et al. 2017).
• Accordingly, TAMs secrete cytokines such as IL-10 (Ng et al. 2013) and TGF-β (McIntire et al. 2004) that induce immunosuppression, impairing the activity of effector T cells and inhibition of dendritic cell (DC) maturation (Rubtsov et al. 2008).
• TAMs also directly stimulate cancer cell proliferation through the secretion of epidermal growth factor (EGF) (O'Sullivan et al. 1993), promote tumor angiogenesis by vascular EGF (VEGF) secretion (Shojaei et al. 2008), and remodel the ECM by secreting metalloproteinases (MMPs) (Kessenbrock et al. 2010).
• Although TAMs mostly play protumorigenic roles, they can also sometimes exert anti-tumoral roles. For example, nonclassical NR4A1⁺ patrolling monocytes that, in steady state conditions, are located in the microvasculature of different organs inhibit lung metastasis in MMTV-PyMT mice by direct induction of NK cell recruitment to the metastatic site (Hanna et al. 2015). Additionally, TAMs mediate the efficacy of the anti-tumor and anti-metastatic effects of the histone deacetylase inhibitor TMP195, which reprograms TAMs to a highly phagocytic phenotype (Guerriero et al. 2017).
• TAMs are recruited to the tumors by a range of chemokines, including CCL2 (Nakatsumi et al. 2017), VEGF (Qian et al. 2011), CCL5 (Halama et al. 2016), and CSF1 (Abraham et al. 2010).
• The role of VEGF as a proangiogenic and protumor factor is well established and accepted
  *The role of CCL2 in cancer is more controversial, as previous studies have shown contradictory findings
• Likewise, although the M1-like/M2-like paradigm has proved to be useful, transcriptomic analysis suggests that it is likely that a spectrum of differentiated TAMs/MAMs exists and that the current model is oversimplified

细分髓系细胞的文章

• Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer(https://www.sciencedirect.com/science/article/pii/S009286742030341X?via%3Dihub)

Neutrophils（两个亚群，促肿瘤与抑肿瘤）

• Neutrophils are recognized as key players during inflammation. They are among the first immune cells to be recruited to damaged tissue, where they can 8eliminate pathogens and modulate inflammation* by mechanisms such as phagocytosis, secretion of antibacterial proteins, deposit of neutrophil extracellular traps (NETs), and exocytosis of protease-containing granules (Kolaczkowska and Kubes 2013).
• In cancer patients, high levels of tumor-associated neutrophils (TANs), high levels of neutrophilia, and/or high neutrophil/lymphocyte ratios have been associated with an adverse prognosis in different malignances (Keizman et al. 2012; Donskov 2013). #后续关注一下这两篇文章
• Similar to the M1/M2 phenotype of macrophages, it has been proposed that TANs exist in two polarization states, called “N1” and “N2”, to describe protumor and anti-tumor populations, respectively (Fridlender et al. 2009).
• This paradigm is still a matter of debate due to the lack of specific markers to identify these two populations.
• the protumor and anti-tumor functions of TANs are highly context-dependent and likely depend on immune cross-talk with other tumor-associated immune cells.
• In recent years, the presence of NETs in the TME has been linked to cancer progression in animal models and cancer patients. (NETs are extracellular networks released by neutrophils)
  An increase in NET formation has been correlated with progression to metastatic disease in colorectal cancer patients after surgery (Tohme et al. 2016).
• however, a better characterization of the phenotypic heterogeneity and plasticity of cancer-associated neutrophils is needed, considering that they are the most abundant immune cells in circulation.
  The understanding of where and how the neutrophils are programmed or reprogrammed to be protumor and/or anti-tumor will lead to rational designing of targeted therapies.
• In xenograft models of melanoma and lung cancer, TANs expressing hepatocyte growth factor receptor (c-MET) play important anti-tumor and anti-metastatic roles. Interestingly, c-MET expression is induced by tumor-derived tumor necrosis factor-α (TNFα) (Finisguerra et al. 2015), and it is likely that NK and effector T cells are a source of TNF-α within the TME.
  注：TNFα主要由活化的单核/巨噬细胞产生，能杀伤和抑制肿瘤细胞的细胞因子。促进中性粒细胞吞噬，抗感染，引起发热，诱导肝细胞急性期蛋白合成，促进髓样白血病细胞向巨噬细胞分化，促进细胞增殖和分化，是重要的炎症介质，并参与某些自身免疫病的病理损伤。（https://baike.baidu.com/item/%E8%82%BF%E7%98%A4%E5%9D%8F%E6%AD%BB%E5%9B%A0%E5%AD%90-%CE%B1/53307279）

NK cells（杀手）

• NK cells are innate immune cells that display rapid and potent cytolytic activity in response to infected or transformed cells (Cerwenka and Lanier 2016).
• NK cells have a well-documented anti-tumor effect.
• These data highlight the importance of NK cells’ function in controlling cancer progression.

DCs(对NK与Tcell至关重要)

• These specialized antigen-presenting cells (APCs) that represent the interface between innate and adaptive immunity are able to present endogenous and exogenous antigens to T cells in the context of MHC molecules.
• With the exception of the brain parenchyma, DCs are located in every tissue across the body (Mildner and Jung 2014).
• During tumor development, DCs prime naïve and memory T cells, and, depending on the inflammatory context and the costimulatory signals, the antigen presentation can result in antigen tolerance or priming and triggering of an effector T-cell response.
• Tumor-infiltrating DCs have been described in many cancer types (Tran Janco et al. 2015), and, although their activity is necessary to explain the role of T cells during cancer progression, DC involvement in cancer progression remains understudied.(DCs对T细胞很重要)
• Between 1995 and 2004, several clinical trials in phases I, II, and II have tested the use of autologous DCs pulsed with tumor antigens (DC vaccine) to initiate an anti-tumor T-cell response, with promising but limited success, especially in melanoma and prostate cancer
  More recently, a phase II study in 39 melanoma patients showed that the combination of an intradermal DC vaccine combined with CTLA-4 blockade resulted in eight complete and seven partial therapeutic responses (Wilgenhof et al. 2016). #DC疫苗
• Overall, DCs play a key role in the priming and consolidation of anti-tumor adaptive immune response; a better understanding of such mechanisms will shed light on how the anti-tumor T-cell attack fails to eliminate and contain the tumor development.

T cell(Dual role of T cells in cancer and metastasis.)

• T cells are components of the adaptive immune system that act as orchestrators and effectors of immunity.
• Depending on the immunological context, T cells can acquire functional and effector phenotypes whose activity has direct inflammatory or anti-inflammatory consequences. #根据免疫环境获得相应的功能及表型，再发挥相应的作用
• During the early stages of tumor initiation, if enough immunogenic antigens are produced, naïve T cells will be primed in the draining lymph nodes, followed by their concomitant activation and migration to the TME.
• From there, they mount a protective effector immune response, eliminating immunogenic cancer cells. Histopathological analyses of human tumors show that tumor-associated T cells extend beyond the invasive edge of the tumor and also predominate in its hypoxic core.
• A high level of T-cell infiltration in tumors is associated with a favorable prognosis in melanoma (Clemente et al. 1996) and breast (Oldford et al. 2006), lung (Dieu-Nosjean et al. 2008), ovarian (Kusuda et al. 2005), colorectal (Tosolini et al. 2011), renal (Kondo et al. 2006), prostate (Vesalainen et al. 1994), and gastric (Ubukata et al. 2010; Fridman et al. 2012; Kitamura et al. 2015) cancer.

CD8+ T cells

• CD8+ T cells are the most prominent anti-tumor cells. ##重点啊
• Upon priming and activation by APCs, the CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs) and, through the exocytosis of perforin- and granzyme-containing granules, exert an efficient anti-tumoral attack, resulting in the direct destruction of target cells.
• The presence of tumor-infiltrating CD8+ T cells and Th-1 cytokines in tumors correlates with a favorable prognosis in terms of overall survival and a disease-free survival in many malignancies (Fridman et al. 2012).

CD4+ T helper 1 (Th-1) cell

• Meanwhile, the CD4+ T helper 1 (Th-1)-mediated anti-tumoral response—through secretion of high amounts of proinflammatory cytokines such as IL-2, TNF-α, and IFN-γ—promotes not only T-cell priming and activation and CTL cytotoxicity but also the anti-tumoral activity of macrophages and NK cells and an overall increase in the presentation of tumor antigens.

If the T cells are highly effective at killing malignant transformed cells, how do some cancer cells manage to overcome the attack by these effector T cells?

• Preclinical investigations in patients and mouse models suggest that cancer cells exploit the immunosuppressive properties of T cells while impairing the effector functions of anti-tumor T cells, such as their ability to infiltrate tumors and their survival, proliferation, and cytotoxicity.
• The nature of the effector T cells implies that the effectiveness of the anti-tumor T-cell immune response depends on both the ability of the tumor antigen to induce an immune response (immunogenic) and the presence—or absence—of inhibitory signals that can impair the T cells’ functions.
• cancer immune editing
  Accordingly, it is widely accepted that, in a T-cell-dependent process, most neoplastic cells expressing highly immunogenic antigens will be recognized and killed during the early stages of tumor development (Matsushita et al. 2012). The less immunogenic cancer cells escape the immune control of T cells and survive, a process termed cancer immune editing (Teng et al. 2015).
• The final outcome is that the surviving cancer cells adopt an immune-resistant phenotype. In parallel, during tumor development, cancer cells evolve mechanisms that mimic peripheral tolerance and are able to prevent the local cytotoxic response of effector T cells as well as those of other cells, such as TAMs, NK cells, and TANs.
  
  p3.png
  Dual role of T cells in cancer and metastasis. During the early stages of tumorigenesis, the T-cell response against tumor-derived antigens controls tumor progression, characterized by secretion of Th-1 cytokines (IFN-γ, IL-2, and IL-12), NK cell recruitment, and the presence of CTLs. As a consequence of the constant selective pressure of the effector response, tumor variants are selected and escape immune recognition. These tumor cells enter a phase of outgrowth that is not blocked by effector immune cells. Concomitantly, the tumor induces the recruitment of regulatory CD4+ T cells (Tregs) that counteract anti-tumor immune cells by diverse mechanisms. Tumors with high infiltration of Tregs are associated with the worst prognosis. For abbreviations and further details, see the text.

Mechanism of peripheral tolerance

• During immune homeostasis, a crucial mechanism of peripheral tolerance is the regulation of effector T-cell response via immune checkpoints on CTLs and activated CD4+ T cells to protect tissue from inflammatory damage. The two better described checkpoint molecules CTLA-4 and PD-1 act as negative regulators of T-cell function and have been associated with immune evasion in cancer.
• Furthermore, the engagement of PD1 with its coreceptor, PDL-1 (expressed by other immune cells, mesenchymal cells, vascular cells, and cancer cells), results in the down-regulation of T-cell activity, which inhibits their anti-tumor activities such as T-cell migration, proliferation, secretion of cytotoxic mediators, and restriction of cell killing (Topalian et al. 2015).
• Over the past few years, the use of immune checkpoint inhibitors such as anti-PD1 (pembrolizumab and nivolumab), anti-PD-L1 (MPDL3280A), and anti-CTLA4 (ipilimumab) has had remarkable success enhancing the effector anti-tumor response in different malignancies (Gotwals et al. 2017), especially in melanoma and lung cancer (Hamid et al. 2013; Herbst et al. 2014; Topalian et al. 2015).

• As the tumor grows and the TME changes, new antigens are produced, and the ability of the immune system to prime new repertoires of T cells and direct them toward the tumor changes, thus altering the efficacy of tumor containment.
• As the immune system functions to stall tumor growth, cancer cells and the TME simultaneously suppress anti-tumor function by engaging immune checkpoints and the recruitment of regulatory CD4+ T cells (Tregs). #免疫逃逸机制有两个，一个是与免疫检查点结合，逃避T细胞的追杀，另一个是招募Treg细胞，抑制免疫反应
  Tregs are responsible for suppressing the priming, activation, and cytotoxicity of other effector immune cells, such as Th1 CD4 T cells, CTLs, macrophages, NK cells, and neutrophils (Ward-Hartstonge and Kemp 2017).
  The Treg-mediated immunosuppression is orchestrated by contact-dependent mechanisms such as the expression of PDL-1, LAG-3, CD39/73, CTLA4, or PD1, with the latter two even enhancing suppressive activity (Walker and Sansom 2015), and by contact-independent mechanisms, which involve the sequestration of IL-2 and production of immune-suppressive molecules such as IL-10, TGF-β, prostaglandin E2, adenosine, and galectin-1 (Francisco et al. 2009; Campbell 2015).
• On the other hand, a high level of circulating Tregs has been associated with a higher risk of metastasis in non-small lung carcinoma patients. (Erfani et al. 2012). Similar associations have been described in breast cancer (Metelli et al. 2016), colorectal carcinoma metastasis (Wang et al. 2014), and hepatocellular carcinoma (Ye et al. 2016).

Invariant NK T (iNKT) cells（杀手）

• An unconventional subset of T cells, iNKT cells, recognizes lipid antigens presented by CD1d molecules and shares some characteristics with NK cells, among which is the potential for activation in the absence of TCR stimulation. Upon activation, iNKT cells secrete effector cytokines such as IFN-γ, IL-4, and IL-17.
  注：CD1D is the human gene that encodes the protein CD1d, a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.(https://en.wikipedia.org/wiki/CD1D)

B cells(促肿瘤？)

B cells may be a double-edged sword, resulting either in tumor cell destruction by increasing T cell responses and via ADCC or in tumor growth by fueling chronic inflammation, angiogenesis, or immunosuppression via immune complex formation or complement activation.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754675/)

• Upon activation in the germinal centers in lymphoid organs, B cells expressing high-affinity antibodies differentiate into antibody-secreting plasma cells and memory B cells that mediate humoral immunity against pathogens (De Silva and Klein 2015).
• Accumulating evidence indicates that B cells promote and support tumor growth #这个结果与常识相悖，B cell竟然是protumor cell?
• The subsets of B cells that induce immunosuppression are termed regulatory B cells due to their function, although there is no consensus about this classification due to the lack of specific markers, similar to FoxP3 and CD25 in Tregs.

Cross-talk between immune cells sculpts the response to the tumor

• There is growing evidence that tumor-associated immune cells act in concert to both control and promote the tumor formation.

during the phase of elimination

• during the phase of elimination, NK cells exert a strong tumoricidal role; secretion of CCL5 and XCL1 by NK cells promotes the recruitment of conventional DCs (cDCs) to the TME, resulting in increased priming and activation of new repertoires of anti-tumor T cells, stimulating the overall effector immune response (Moretta et al. 2005; Bottcher et al. 2018).
  Additionally, the reciprocal interplay between NK cells, effector T cells, and anti-tumor macrophages by the secretion of IFN-γ and TNF-α in the tumor site boosts the differentiation of CTLs, increases macrophage phagocytosis, increases the recruitment of cytotoxic cMET⁺ neutrophils, and enhances the cytotoxic ability of NK cells (Finisguerra et al. 2015; Showalter et al. 2017).
• Dectin-1, a pattern recognition receptor on macrophages and DCs, recognizes N-glycan structures on tumor cells, which activate the IRF5 pathway responsible for enhancing the killing capacity of NK cells (Chiba et al. 2014).
  注：Dectin-1 belongs to the hemITAM family and can be found in the plasma membrane of various myeloid cells, including DCs, monocytes, and macrophages, as well as B cells. Activation of dectin-1 by fungal cell wall β-glucans stimulates phagocytosis, the production of ROS, and NFκB-mediated cytokine secretion.
• Moreover, CX3CR-1⁺ patrolling monocytes inhibit metastatic progression through the recruitment of NK cells to the metastatic site, and then NK cell-derived IFN-γ reprograms macrophages into a tumoricidal effector macrophage state (O'Sullivan et al. 2012).

tumors have escaped from initial tumoricidal immunity(从免疫杀伤阶段转到免疫耐受阶段)

• Once the tumors have escaped from initial tumoricidal immunity, they undergo different strategies that tip the balance toward immune tolerance, with the TAMs and tumor-associated Tregs as key orchestrators of this process, as they dampen the effect of innate and adaptive effector immune cells at various levels and through different mechanisms.
• For example, TAMs and Tregs boost an immune-tolerant TME by secretion of immune-suppressive molecules such as IL-10, TGF-β, and prostaglandins; they also inhibit the secretion of IL-12 by DCs, avoiding the mounting of a Th-1 response and excluding NK and effector T cells (Ruffell et al. 2014; Speiser et al. 2016; Frydrychowicz et al. 2017; Mantovani et al. 2017; Tauriello et al. 2018).
• subsequent analysis showed that the efficacy was dependent on an orchestrated response of both innate and adaptive immune cells (Moynihan et al. 2016).

Cancer heterogeneity and anti-tumor immunosurveillance（省略）

How tumor cells evade the immune response

• Tumor cells evade the immune attack using two main strategies: avoiding the immune recognition and instigating an immunosuppressive TME.
• In the first, cancer cells may lose the expression of tumor antigens on the cell surface, thus avoiding the recognition by cytotoxic T cells. For example, 40% of non-small cell lung cancers hold a loss of heterozygosity in human leukocyte antigens (HLAs), which leads to immune escape by presenting fewer antigens (McGranahan et al. 2017). Notably, HLA loss has been associated with resistance to T-cell transfer therapy in metastatic colorectal cancer (Tran et al. 2016) and poor outcome response to checkpoint blockade immunotherapy in melanoma and lung cancer patients (Chowell et al. 2018). In this sense, mutations and deletions may result in down-regulation of the antigen-presenting machinery and likely confer resistance to T-cell effector molecules such as TNF-α and IFN-γ (Patel et al. 2017). Additionally, to overcome the attack of NK cells in experimental metastasis, breast and lung cancer cells down-regulate cell surface NK activators, becoming invisible to detection by NK cells (Malladi et al. 2016).
• In the second, cancer cell-derived factors instigate an immune-tolerant TME by (1) secretion of suppressive molecules such as IL-10, TGF-β, prostaglandin E2, and VEGF (Gabrilovich et al. 1996; Massague 2008; Dominguez-Soto et al. 2011; Bottcher et al. 2018); (2) expression of inhibitory checkpoint molecules such as PD-L1, CTLA-4, and V domain immunoglobulin suppressor of T-cell activation (VISTA) (Topalian et al. 2012; Snyder et al. 2014; Boger et al. 2017); and (3) induction of the recruitment of TAMs, MDSCs, and Tregs by tumor-derived chemokines such as CCL2, CSF1, CCL5, CCL22, CXCL5, CXCL8, and CXCL12(Weitzenfeld and Ben-Baruch 2014; Kumar et al. 2016; Mantovani et al. 2017; Tanaka and Sakaguchi 2017). Combined, these strategies result in a complex and efficient system for immune evasion. Therefore, multimodal therapies aimed at disrupting different aspects of the immune-tolerant apparatus in cancer may improve the efficiency of current immunotherapies. In this regard, two studies showed recently that the TGF-β blocking increases the therapeutic response of anti-PD-L1 therapy, resulting in tumor regression in EMT6 breast carcinoma models (Mariathasan et al. 2018) and complete elimination of established liver metastases from a colorectal cancer model (Tauriello et al. 2018).

结合治疗策略

Challenges in studying cancer-associated inflammatory cells（省略）

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