结直肠癌免疫微环境中肿瘤相关巨噬细胞的作用

结直肠癌（colorectal cancer,CRC）的发生、发展不仅与肿瘤细胞本身的特性相关,也与肿瘤微环境（tumor microenvironment,TME）密切相关。肿瘤细胞及其微环境通过分泌多种细胞因子,将循环血液中的单核细胞招募至TME并使其极化为肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）。作为TME中最丰富的免疫细胞之一,TAMs的功能和特点与M2型巨噬细胞相似,TAMs主要具有刺激肿瘤细胞增殖、血管生成、基质重塑和促进肿瘤细胞侵袭及转移等作用。在多数肿瘤中,TAMs主要发挥促肿瘤作用并与患者的不良预后相关;但在CRC中,TAMs的作用仍存争议。本文主要就CRC免疫微环境中TAMs的作用及其机制进行综述,以展示TAMs对CRC患者的病程进展及预后的影响并探讨TAMs作为CRC免疫治疗靶点的可行性。      

肿瘤免疫微环境中的NK细胞及免疫治疗

自然杀伤（NK）细胞是一类具有强大抗肿瘤功能的固有淋巴细胞,能够快速识别和杀伤肿瘤细胞,其功能受活化性受体和抑制性受体的多种信号所调控。但是,肿瘤浸润NK细胞的杀伤功能由于免疫抑制性肿瘤微环境而失调,甚至会促进肿瘤细胞的免疫逃逸,导致多种免疫疗法临床治疗的效果不佳。肿瘤细胞上调表达抑制性配体、肿瘤微环境中大量抑炎因子及异常的低氧、低pH等,都诱导肿瘤浸润NK细胞杀伤功能受损。近年来,关于肿瘤微环境与肿瘤浸润NK细胞的研究正处于肿瘤免疫领域的前沿,已经取得了很多临床研究成果。多项研究表明,肿瘤浸润NK细胞通常表现为抑制性受体上调、活化性受体下调和代谢异常等特征,基于此,研究者开发了多种针对性治疗方案,以恢复NK细胞的杀伤能力。本文在阐述NK细胞功能活化和抑制相关机制的基础上,论述了肿瘤浸润NK细胞的特征及其相应的肿瘤免疫治疗方案。     

调节性T细胞在结直肠癌发生发展中的作用及相关治疗

调节性T细胞（regulatory T cell,Treg）是肿瘤微环境中重要的免疫抑制性细胞,在维持免疫稳态方面发挥重要的作用。Treg不仅可以通过分泌抑制性细胞因子阻碍有效的抗肿瘤免疫,还可以通过调节细胞因子进而调控结直肠癌（colorectal cancer,CRC）细胞生长,同时直接或间接地促进CRC血管新生,并与患者不良预后有关;但Treg也可能在炎症相关性肿瘤发生的早期,通过抑制炎症反应降低肠道肿瘤发生的风险。近年来,靶向Treg的免疫治疗也成为了研究热点,一些治疗策略已经在临床应用,还有一些正在进行临床前及临床试验。本文就Treg在CRC发生发展中的作用及靶向Treg的免疫治疗策略进行综述,探讨Treg作为治疗靶点的作用机制及临床应用前景。      

The tumor microenvironment drives NK cell metabolic dysfunction leading to impaired antitumor activity

NK cells represent key players capable of driving antitumor immune responses. However, the potent immunosuppressive activity of the tumor microenvironment (TME) may impair their effector function. Here, we strengthen the importance of metabolic interactions between NK cells and TME and propose metabolic dysfunction as one of the major mechanisms behind NK failure in cancer treatment. In particular, we described that TME has a direct negative impact on NK cell function by disrupting their mitochondrial integrity and function in pediatric and adult patients with primary and metastatic cancer. Our results will help to design new strategies aimed at increasing the NK cell antitumor efficacy by their metabolic reprogramming. In this regard, we reveal an unprecedented role of IL15 in the metabolic reprogramming of NK cells enhancing their antitumor functions. IL15 prevents the inhibitory effect of soluble factors present in TME and restores both the metabolic characteristics and the effector function of NK cells inhibited by exposure to malignant pleural fluid. Thus, we propose here that IL15 may be exploited as a new strategy to metabolically reprogram NK cells with the aim of increasing the efficacy of NK-based immunotherapy in a wide range of currently refractory adult and pediatric solid tumors.     

Immune mediators in the tumor microenvironment of prostate cancer

Prostate cancer tissue is composed of both cancer cells and host cells. The milieu of host components that compose the tumor is termed the tumor microenvironment (TME). Host cells can be those derived from the tissue in which the tumor originates (e.g., fibroblasts and endothelial cells) or those recruited, through chemotactic or other factors,to the tumor (e.g., circulating immune cells). Some immune cells are key players in the TME and represent a large proportion of non-tumor cells found within the tumor. Immune cells can have both anti-tumor and pro-tumor activity.In addition, crosstalk between prostate cancer cells and immune cells affects immune cell functions. In this review,we focus on immune cells and cytokines that contribute to tumor progression. We discuss T-regulatory and T helper 17 cells and macrophages as key modulators in prostate cancer progression. In addition, we discuss the roles of interleukin-6 and receptor activator of nuclear factor kappa-B ligand in modulating prostate cancer progression. This review highlights the concept that immune cells and cytokines offer a potentially promising target for prostate cancer therapy.     

Exosomes: Mediators in microenvironment of colorectal cancer

Tumor microenvironment, the soil where tumor thrives, plays a critical role in the development and progression of colorectal cancer (CRC). Various cell signaling molecules in the environment promote tumor angiogenesis, immune tolerance and facilitate immune escape. Exosomes, as messengers between tumor and host cells, are considered key mediators involved in the tumor-accelerating environment. However, the exosome-mediated communication networks in the CRC microenvironment are still largely unclear. In this review, we summarized the relationship between TME and CRC based on recent literature. Then, we revealed the unique impacts and signal molecules of exosomes on account of their regulatory role in the flora, hypoxia, inflammatory and immunological microenvironment of CRC. Finally, we summarized the therapeutically effective of exosomes in CRC microenvironment and discussed their current status and prospects, aiming to provide new molecular targets and a theoretical basis for the CRC treatment.     

肿瘤免疫抑制微环境对肿瘤免疫治疗作用的研究进展

肿瘤免疫抑制微环境是肿瘤微环境中起抑制免疫功能的部分。其组成包括抑制性细胞和抑制性细胞因子。近年来,因其在肿瘤免疫中的重要作用,CAR－T和PD－1／PD－L1信号通路已成为免疫治疗的研究热点,它们可通过不同的机制产生免疫抑制作用,从而促进肿瘤进展。因此,针对以上机制采取更有效的抗肿瘤疗法有可能减缓肿瘤进展。本文现就免疫抑制微环境对CAR－T疗法和PD－1／PD－L1信号通路在抗肿瘤过程中的作用进行综述。     

树突状细胞临床治疗实体瘤：峰回路转

肿瘤免疫细胞疗法展现了良好的临床抗肿瘤前景。树突状细胞（DC）识别肿瘤抗原作为机体免疫响应的关键起始步骤,捕获肿瘤抗原后分化成熟,在淋巴结将抗原信号提呈给CD4+ T细胞、CD8+ T细胞等免疫细胞,激发抗肿瘤效应,应用于肿瘤治疗,尤其是实体瘤,被寄予厚望。但由于实体瘤TME复杂的结构特点、DC和T/B 细胞免疫响应的机制不清晰等问题犹如崇山峻岭摆在眼前,故未能形成关键理论和技术突破。以CAR-T 细胞为代表的精准细胞免疫疗法已表现出优势,但仍面临抗原选择瓶颈。DC治疗性疫苗在临床试验中表现出良好的疗效和安全性,随着DC在TME中关键作用机制的进一步揭示,研究者的目光重新聚焦在DC抗肿瘤效应,推动着DC与其他手段的联合疗法、工程化DC疫苗等实体瘤治疗方案从基础向临床转化,目前正迈入DC临床治疗实体瘤的新阶段。本文系统地对DC治疗实体瘤的临床研究进展、实体瘤TME中DC的种类及其抗肿瘤机制、工程化DC疫苗,以及面临的挑战和应对策略等问题进行了评述。     

Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review)

The resistance of many human cancers to immune-based therapies, including adoptive immunotherapy and the administration of therapeutic cancer vaccines, has been attributed to tumor-associated immune suppression, due in part to immunosuppressive molecules located within the tumor microenvironment. Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells. It is well established that extracellular adenosine inhibits T lymphocyte activation and effector function, including T cell adhesion to tumor cells and cytotoxic activity, by signaling primarily through A2a and A3 adenosine receptors on the surface of T cells. Importantly, A2a adenosine receptor-deficient mice exhibit enhanced anti-tumor immune responses by CD8+ T cells, as well as a dramatic reduction in the growth of experimental tumors in comparison to wild-type controls. A2a adenosine receptor signaling has also been implicated in adenosine-mediated inhibition of cytokine production and cytotoxic activity by activated natural killer (NK) cells, although the process of NK cell granule exocytosis is apparently suppressed via a distinct and as yet uncharacterized adenosine receptor. In this report, we review the evidence that adenosine is a potent inhibitor of cellular immune responses and may therefore be a major barrier to the successful immunotherapy of human carcinomas. The signaling pathways through which adenosine exerts its inhibitory effects on cell-mediated immune responses are also discussed. The accumulated evidence suggests that the effectiveness of immune-based therapies for solid tumors may be enhanced by selective antagonism of the adenosine receptor subtypes through which adenosine inhibits the anti-tumor activity of T lymphocytes and NK cells.     

CAR-T细胞治疗突破实体肿瘤微环境新策略的研究进展

免疫治疗可通过提高患者自身免疫力以达到抗肿瘤目的,其中嵌合型抗原受体修饰T细胞(chimeric antigen receptor modified T cells,CAR-T)在血液系统肿瘤中已显现出良好疗效。实体肿瘤微环境(tumor microenvironment,TME)中免疫抑制细胞及分子等可限制CAR-T细胞在肿瘤部位浸润及其在浸润部位产生细胞毒作用。因此CAR-T细胞治疗在血液系统肿瘤中的显著疗效未在实体肿瘤中呈现。本文就如何突破TME限制,提高CAR-T细胞归巢能力及细胞毒作用,从而提高其在实体瘤中的疗效做一综述。     

The tumor microenvironment of lymphomas: Insights into the potential role and modes of actions of checkpoint inhibitors

The tumor microenvironment (TME) – a term comprising non‐neoplastic cells and extracellular matrix as well as various cytokines, chemokines, growth factors, and other substances in the vicinity of tumor cells – is an integrative part of most tumors including lymphomas. Interactions between lymphoma cells and the TME are vital for survival and proliferation of the former. In addition, lymphoma cells often reprogram the TME to protect them from defense mechanisms of the host's immune system. In this review, we will introduce the role of the tumor microenvironment (TME) for lymphoma cells looking at direct cell–cell interactions as well as cytokine‐related communications. The immunomodulative/immunosuppressive role of the TME is more and more coming into the focus of potential new targeted therapies, and thus a special attention will be given to the interactions of immune checkpoints such as programed cell death protein 1 and L1 (PD‐1/PD‐L1), T‐cell immunoglobulin and mucin‐domain containing protein‐3 (TIM‐3), lymphocyte‐activation gene 3 (LAG‐3), and cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA4) with the TME, as well as their expression by both lymphoma cells and cells of the TME. Aspects of the TME will be discussed for indolent and aggressive B‐cell lymphomas, Hodgkin lymphomas, and T‐cell lymphomas. In addition, the potential influence of other immunomodulators such as lenalidomide will be briefly touched. The complex role of the TME is in the focus of new therapeutic options. In order to exploit its full therapeutic potential, however, a thorough understanding of TME biology and interaction between lymphoma cells and the TME, as well as the host's immune system and the TME is necessary.     

Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN‐γ and induces NK cell‐dependent lymphoma control without other immunotherapies

Like other immune cells, natural killer (NK) cells show impaired effector functions in the microenvironment of tumors, but little is known on the underlying mechanisms. Since lactate acidosis, a hallmark of malignant tissue, was shown to contribute to suppression of effective antitumor immune responses, we investigated the impact of tissue pH and lactate concentration on NK‐cell functions in an aggressive model of endogenously arising B‐cell lymphoma. The progressive loss of IFN‐γ production by NK cells observed during development of this disease could be ascribed to decreased pH values and lactate accumulation in the microenvironment of growing tumors. Interestingly, IFN‐γ expression by lymphoma‐derived NK cells could be restored by transfer of these cells into a normal micromilieu. Likewise, systemic alkalization by oral delivery of bicarbonate to lymphoma‐developing mice was capable of enhancing IFN‐γ expression in NK cells and increasing the NK‐cell numbers in the lymphoid organs where tumors were growing. By contrast, NK‐cell cytotoxicity was dampened in vivo by tumor‐dependent mechanisms that seemed to be different from lactate acidosis and could not be restored in a normal milieu. Most importantly, alkalization and the concomitant IFN‐γ upregulation in NK cells were sufficient to significantly delay tumor growth without any other immunotherapy. This effect was strictly dependent on NK cells.     

Loss of cancer cell-derived ADAM15 alters the tumor microenvironment in colorectal tumors

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.     

Immunogenic cell death in colon cancer prevention and therapy

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The colonic mucosa constitutes a critical barrier and a major site of immune regulation. The immune system plays important roles in cancer development and treatment, and immune activation caused by chronic infection or inflammation is well-known to increase cancer risk. During tumor development, neoplastic cells continuously interact with and shape the tumor microenvironment (TME), which becomes progressively immunosuppressive. The clinical success of immune checkpoint blockade therapies is limited to a small set of CRCs with high tumor mutational load and tumor-infiltrating T cells. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, can therefore help break the immunosuppressive TME, engage the innate components, and prime T cell-mediated adaptive immunity for long-term tumor control. In this review, we discuss the current understanding of ICD induced by antineoplastic agents, the influence of driver mutations, and recent developments to harness ICD in colon cancer. Mechanism-guided combinations of ICD-inducing agents with immunotherapy and actionable biomarkers will likely offer more tailored and durable benefits to patients with colon cancer.     

Dendritic Cell Cancer Vaccines for Treatment of Colon Cancer

Despite advances in treatment modalities, colorectal cancer (CRC) still accounts for about half a million deaths yearly worldwide. The majority of metastatic CRC are unresectable, and of those who undergo resection, few are cured. Advances in chemotherapy and targeted therapy have improved survival, but options remain limited, making the case for incorporating novel modalities in CRC treatment paradigm. Our improved understanding of the tumor immune microenvironment had led to the development of novel immunotherapeutic agents that have been tested in clinical trials such as cancer vaccines. Cancer vaccines are designed to activate the effector immune cells in order to generate an immune response against tumors. Dendritic cell vaccines offer potential benefits for CRC patients but requires further evaluation. We reviewed the role of dendritic cells in the colorectal tumor microenvironment and dendritic cancer vaccine studies in colorectal cancer.     

NK细胞极化在子宫内膜癌中的作用

自然杀伤(Natural killer,NK)细胞是一类具有细胞毒性的固有免疫细胞,被认为是主要的抗肿瘤效应细胞,但是NK细胞的功能在肿瘤的进展过程中发生了巨大的变化。子宫内膜癌(Endometrial cancer,EC)是女性生殖系统中最常见的肿瘤之一,免疫逃逸机制是EC进展的基础。在子宫内膜癌微环境中,细胞毒性NK细胞向肿瘤部位的募集减少,表型改变,杀伤功能降低,从而促进肿瘤生长和肿瘤血管生成。如何避免极化的微环境损害NK细胞的毒性,并且抑制促进肿瘤生长的NK细胞,成为我们关注的重点。     

Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review

Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response. There may be three reasons. First, the complex tumor microenvironment of cold colorectal cancer(CRC) leads to tolerance and clearance of immunotherapy. Second, the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption. Finally, the difference in number and function of immune cell subsets in patients with cold CRC mak...     

NKG2D ligand expression in pediatric brain tumors

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.     

Early activation and interferon-γ production of tumor-infiltrating mature CD27 high natural killer cells

Natural killer (NK) cells are known to be critically involved in the control of tumors through their direct cytotoxic function, but have also been proposed as an initial source of interferon (IFN)-γ that primes subsequent adaptive tumor-specific immune responses. Although mounting evidence supports the importance of NK cells in antitumor immune responses, the immunological characteristics of NK cells infiltrating the tumor microenvironment and the mechanisms that regulate this process remain unclear. In the present study, we found that NK cells infiltrate early developing MCA205 tumors, and further showed that mature CD27(high) NK cells were the predominant subpopulation of NK cells accumulating in the tumor microenvironment. The tumor-infiltrating NK cells displayed an activated cell surface phenotype and provided an early source of IFN-γ. Importantly, we also found that host IFN-γ was critical for NK cell infiltration into the local tumor site and that the tumor-infiltrating NK cells mainly suppressed tumor growth via the IFN-γ pathway. This work implicates the importance of IFN-γ as a positive regulatory factor for NK cell recruitment into the tumor microenvironment and an effective antitumor immune effector response.