代谢重编程介导肿瘤免疫微环境重塑的现状和展望

代谢重编程是肿瘤的特征之一,也是肿瘤治疗的重要潜在靶点。肿瘤和免疫细胞之间的相互作用对代谢重编程的影响是决定抗肿瘤免疫应答的关键因素之一。肿瘤代谢不仅在肿瘤发生和维持肿瘤细胞生存中发挥了关键作用,并且可以通过释放代谢产物,如乳酸、PGE2等来影响免疫细胞进而影响肿瘤免疫微环境。这种肿瘤细胞与免疫细胞之间的相互作用导致了肿瘤免疫微环境中的代谢竞争,限制了营养物质的正常代谢,形成酸性环境,最终导致抗肿瘤免疫反应减弱和免疫抑制性微环境的形成。此外,免疫细胞发生免疫应答的过程中存在代谢方式的改变,即在增殖、分化和执行细胞功能的过程中会发生代谢重编程。因此,了解肿瘤免疫微环境中肿瘤细胞和免疫细胞的代谢重编程的调节机制,可以使研究人员在抗肿瘤免疫治疗中获得靶向代谢途径的治疗思路。     

肿瘤免疫微环境在肿瘤常规治疗效应中的作用

机体免疫系统能识别和杀伤恶变的细胞,从而清除肿瘤细胞或控制其生长.在机体免疫选择压力下,肿瘤细胞可以依靠自身的高突变特性,逃避免疫监视,逐步建立起免疫抑制微环境,以抵抗和抑制机体抗肿瘤免疫反应,从而能够突破限制而持续扩增,最终发展成为临床可见的肿瘤.目前肿瘤治疗的策略主要是着眼于直接抑制肿瘤细胞增殖以及杀伤和清除肿瘤细胞,然而越来越多的研究结果表明,常规治疗导致的肿瘤细胞免疫原性死亡,可以激活先天性免疫信号通路,诱发机体内在的抗肿瘤免疫反应,在肿瘤治疗效应中起着关键作用,尤其对防止残存肿瘤细胞的复发具有非常重要的意义.本文概述肿瘤发生、发展和常规治疗过程中,机体抗肿瘤免疫反应与肿瘤免疫抑制微环境的细胞和分子机制,重点讨论两者在肿瘤常规治疗效应中的作用,解析以肿瘤免疫微环境为靶点的治疗策略,讨论该策略对提高目前肿瘤常规治疗疗效和发展新的肿瘤治疗方案的积极意义.     

骨髓源性抑制细胞在肿瘤免疫治疗中的研究进展及与肺癌预后的关系

免疫治疗是肺癌新兴治疗方法,其疗效受肿瘤免疫微环境（tumor immune microenvironment,TIME）影响。骨髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是免疫微环境的主要免疫抑制细胞,在肿瘤的发生、发展、侵袭和转移过程中起关键作用。近年来,探索克服MDSCs的免疫抑制,从而增强抗肿瘤治疗疗效的研究已经成为研究热点。在这篇综述中,我们讨论了靶向MDSCs以及与ICI联合治疗的进展,并总结了MDSCs对肺癌患者预后的影响。     

A review of immune checkpoint blockade in breast cancer

In the recent years characterized by the cancer immunotherapy revolution, attention has turned to how to potentially boost and/or generate an efficient anti-tumor immune response in breast cancer (BC). Clinical activity of immune checkpoint blockade (ICB) targeting PD-1 or PD-L1 in BC has been more evident in the triple negative subtype and in earlier lines of the treatment. Remarkably, some responders to single agent ICB have achieved durable responses with metastatic disease, possibly as a result of treatment-induced immunological memory. However, most BC are immunologically quiescent and current research efforts developing ICB combinations are attempting to convert “cold” into “hot” tumors by manipulating the tumor microenvironment, expanding anti-tumor T cells improving efficient antigen presentation, and suppressing pro-tumor inhibitory cells. The aim of this review is to summarize existing data on the efficacy of immune checkpoint blockers as single agents and combination strategies in all BC subtypes, highlighting the BC subgroups that benefit most from ICB.     

树突状细胞在肿瘤免疫和免疫治疗中的研究进展

树突状细胞（dendritic cells,DCs）是一类特殊的抗原呈递细胞,在先天和适应性免疫应答的启动和调节中起关键作用。了解DCs的功能以及肿瘤微环境对DCs的影响,有助于开发新的癌症治疗策略。通过调节DCs的功能改善肿瘤免疫治疗的疗效是目前研究的热点。大量研究表明,靶向肿瘤微环境中的DCs是癌症治疗极具前景的方法。本文重点讨论DCs在肿瘤免疫中的主要功能及靶向DCs在癌症中的治疗潜力。     

Dendritic cell-tumor cell hybrids enhance the induction of cytotoxic T lymphocytes against murine colon cancer: a comparative analysis of antigen loading methods for the vaccination of immunotherapeutic dendritic cells

Dendritic cells (DCs) have been used successfully for inducing effective anti-tumor immune responses in advanced cancer patients undergoing tumor-specific immunotherapy. Appropriate antigen pulsing is a crucial parameter for optimizing the efficacy of immunotherapy as well as anti-tumor protection therapy. Using a murine colon cancer model, we evaluated the anti-tumor efficacy of four different preparations of DC vaccines that contained either a whole tumor or its derivatives, including i) DCs pulsed with tumor lysate, ii) DCs pulsed with necrotic tumor cells, iii) DCs pulsed with apoptotic tumor cells, and iv) DC-tumor cell fusion hybrids. Our data show that DC-tumor cell fusion hybrids and DCs pulsed with irradiated apoptotic tumor cells were more potent than DCs with freeze-thawed necrotic tumor cells for the induction of protective anti-tumor responses. The vaccination of DCs pulsed with tumor lysate failed to elicit any anti-tumor effect. In animals administered with higher doses of a tumor-cell challenge, DC-tumor cell fusion hybrids elicited the most effective anti-tumor response. Among the preparations tested, mice immunized with DC-tumor cell fusion hybrids resulted in the greatest induction of cytotoxicity as measured by the cytotoxic T lymphocyte activity of both the splenocytes and the Thy1.2-positive T lymphocytes. Furthermore, the in vitro production of IFN-gamma polarized to the Th1 cytokine responses was highest in the splenocytes derived from mice vaccinated with DC-tumor cell fusion hybrids. Our results suggest that DC-tumor cell fusion hybrids are more potent inducers of protection against solid tumors, such as colon cancer, than other antigen-loading strategies using whole tumor cell materials.     

胰腺癌抑制性免疫微环境促进肿瘤细胞化疗耐药的研究进展

胰腺癌微环境中存在多种免疫抑制细胞,表达不同的细胞因子抑制机体的免疫杀伤功能,在肿瘤发展中发挥重要的作用。这些细胞还能影响化疗药物杀伤肿瘤细胞的功能,促进肿瘤细胞耐药。吉西他滨、白蛋白结合型紫杉醇等胰腺癌一线化疗药物不仅可直接抑制肿瘤细胞增殖,还可作用于免疫细胞间接增强抗肿瘤作用。相反,化疗药物也能增强免疫抑制细胞功能,诱导耐药,促进肿瘤进展。本文就胰腺癌微环境的免疫抑制状态,及其与化疗药物之间作用机制做一综述,旨在从肿瘤免疫微环境的角度优化现有的化疗策略。      

树突状细胞在肿瘤中的研究进展

肿瘤的发生、发展与机体免疫状态密切相关。树突状细胞(DCs)是众多免疫细胞中的一种,具有专职抗原提呈功能,在肿瘤免疫过程中发挥关键的调节作用。肿瘤机体中DCs处于异常状态,如成熟障碍、功能异常和表型改变等,无法激活抗肿瘤的特异性免疫反应。目前,基于DCs的肿瘤免疫疗法备受关注,例如通过促进DCs成熟或者利用修饰过的DCs激活机体靶向肿瘤的免疫反应。本文拟对肺癌、结直肠癌、乳腺癌及肝癌等肿瘤中DCs异常相关机制研究以及临床关于DCs疫苗的研究作一综述。     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)

The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)–targeted therapy has demonstrated the importance of the PD-L1: PD-1 interaction in inhibiting anticancer T-cell immunity in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1–targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1–targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.     

Immunity and malignant mesothelioma: from mesothelial cell damage to tumor development and immune response-based therapies

Malignant mesothelioma (MM) is a cancer with a high mortality rate and limited therapeutic options, typically presenting as a tumor in the serous membranes, most frequently in the pleura and the peritoneum rather than in the pericardium. There is much evidence that the immune system contributes to the biogenesis, growth and metastasis of MM through the unbalanced production of oxidants and cytokines, mesothelial cell DNA damage and the active support of MM neoangiogenesis and immunosuppression. Because classical therapeutic approaches are generally ineffective, novel immunological tools are being developed to target the immune cells infiltrating the MM foci and exploit the immune system to elicit an effective anti-tumor response. These therapies work by stimulating local inflammatory cells or transferring exogenously activated immunocompetent cells and by depleting MM-associated immunosuppressive clones to target the spontaneous specific immune responses against MM and to subvert MM-driven immunoediting. This review summarizes the recent evidence on the immune system mechanisms that support MM development and the novel therapeutic approaches for strengthening the immune system by MM immunotherapy that are currently being developed in both experimental models and clinical trials.     

髓源性抑制细胞联合免疫检查点抑制剂抗肿瘤治疗的研究进展CSCD

免疫检查点抑制剂(ICI)可通过恢复T细胞对肿瘤细胞的识别和损伤功能来增强原有的抗肿瘤免疫应答。ICI已被批准用于黑色素瘤、非小细胞肺癌(NSCLC)和肾细胞癌等多种肿瘤的治疗。然而,许多患者对免疫治疗没有反应。其中部分原因是由髓源性抑制细胞(MDSCs)介导的。这种异质的未成熟骨髓细胞群可以强烈抑制T细胞和NK细胞的抗肿瘤活性并刺激调节性T细胞(Treg)产生免疫抑制,导致肿瘤进展。MDSCs可以促进患者对免疫检查点抑制的耐药。越来越多的证据表明MDSCs在肿瘤患者中的比例和免疫抑制功能可用于治疗反应的预测。本综述重点介绍了MDSCs在免疫检查点抑制中的作用,并提供了MDSCs与ICI靶向联合治疗的策略,以提高后者在肿瘤治疗中的疗效。     

Targeting myeloid-derived suppressor cells for cancer therapy

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.     

Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism,functional regulation,and immunotherapeutic strategies

Tertiary lymphoid structures (TLSs) are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions, including infection, autoimmune disease, and cancer. In the tumor microenvironment (TME), the structures of TLSs, including B-cell- and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers. Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients. It was shown that well-developed TLSs characterized by mature B cells synthesized tumor specific antibodies, which were considered as specific markers for a good prognosis. However, there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses. These factors include dysfunctional B cells, regulatory T cells, and T follicular regulatory cells. The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs; it is therefore essential to fully understand the function and influencing factors in TLSs. It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies. In this review, we focused on recent advances in TLSs in human solid tumors, including structural characteristics and classes, antitumor mechanisms, immunosuppressive factors, and TLS-based therapeutic approaches.     

Dendritic cells respond to nasopharygeal carcinoma cells through annexin A2-recognizing DC-SIGN

Dendritic cells (DCs) play an essential role in immunity and are used in cancer immunotherapy. However, these cells can be tuned by tumors with immunosuppressive responses. DC-specific intercellular adhesion molecule 3-Grabbing Nonintegrin (DC-SIGN), a C-type lectin expressed on DCs, recognizes certain carbohydrate structures which can be found on cancer cells. Nasopharyngeal carcinoma (NPC) is an epithelial cell-derived malignant tumor, in which immune response remains unclear. This research is to reveal the molecular link on NPC cells that induces the immunosuppressive responses in DCs. In this article, we report identification of annexin A2 (ANXA2) on NPC cells as a ligand for DC-SIGN on DCs. N-linked mannose-rich glycan on ANXA2 may mediate the interaction. ANXA2 was abundantly expressed in NPC, and knockdown of ANXA2 suppressed NPC xenograft in mice, suggesting a crucial role of ANXA2 in NPC growth. Interaction with NPC cells caused DC-SIGN activation in DCs. Consequently DC maturation and the proinflammatory interleukin (IL)-12 production were inhibited, and the immunosuppressive IL-10 production was promoted. Blockage of either DC-SIGN or ANXA2 eliminated the production of IL-10 from DCs. This report suggests that suppression of ANXA2 at its expression or glycosylation on NPC may improve DC-mediated immunotherapy for the tumor.     

Anti-tumor immune response induced by dendritic cells transduced with truncated PSMA IRES 4-1BBL recombinant adenoviruses

Up-regulation of receptor–ligand pairs during interaction of a peptide-bound MHC complex on dendritic cells (DCs) with cognate TCR may amplify, sustain, and drive diversity in the ensuing T cell immune response. Members of the TNF ligand superfamily and the TNFR superfamily contribute to this costimulatory molecule signaling. In the present study, we used replication deficient adenoviruses to introduce a tumor-associated Ag (a truncated human prostate-specific membrane antigen (tPSMA)) and the T cell costimulatory molecule 4-1BBL into murine DCs, and observed the ability of these recombinant DCs to elicit tPSMA-directed T-cell responses in vitro and anti-tumor immunity to RM-1-tPSMA in a murine tumor model. Infection of DCs with Ad-tPSMA-IRES-m4-1BBL induced tPSMA-specific proliferative responses and up-regulated CD80 and CD86 s signaling molecules. The cytotoxic T lymphocytes activated by the Ad-tPSMA-IRES-m4-1BBL-transfected DCs showed significantly higher IFN-γ production and cytotoxicity against the RM-1 cells transfected with tPSMA. Moreover, vaccination of mice with Ad-tPSMA-IRES-m4-1BBL-transfected DCs induced a potent protective and therapeutic anti-tumor immunity to RM-1-tPSMA in a tumor model. These results demonstrated that development of DCs engineered to express tPSMA and 4-1BBL by recombinant adenovirus-mediated gene transfer may offer a new strategy for prostate cancer immunotherapy.     

Tumor associated regulatory dendritic cells

Immune effector and regulatory cells in the tumor microenvironment are key factors in tumor development and progression as the pathogenesis of cancer vitally depends on the multifaceted interactions between various microenvironmental stimuli provided by tumor-associated immune cells. Immune regulatory cells participate in all stages of cancer development from the induction of genomic instability to the maintenance of intratumoral angiogenesis, proliferation and spreading of malignant cells, and formation of premetastatic niches in distal tissues. Dendritic cells in the tumor microenvironment serve as a double-edged sword and, in addition to initiating potent anti-tumor immune responses, may mediate genomic damage, support neovascularization, block anti-tumor immunity and stimulate cancerous cell growth and spreading. Regulatory dendritic cells in cancer may directly and indirectly maintain antigen-specific and non-specific T cell unresponsiveness by controlling T cell polarization, MDSC and Treg differentiation and activity, and affecting specific microenvironmental conditions in premalignant niches. Understanding the mechanisms involved in regulatory dendritic cell polarization and operation and revealing pharmacological means for harnessing these pathways will provide additional opportunities for modifying the tumor microenvironment and improving the efficacy of different therapeutic approaches to cancer.     

调节性T细胞诱导肿瘤免疫耐受的机制

调节性T细胞(Treg)是一类免疫抑制性T辅助(Th)细胞.研究表明,Treg可在肿瘤细胞分泌的趋化因子CCL22作用下大量募集于肿瘤周围,分泌或表达免疫抑制性的细胞因子和受体,形成以Th2型免疫为主的微环境,引导宿主免疫耐受.通过抗体等药物降低Treg数量和活性后可打破肿瘤免疫耐受,抑制肿瘤的发生和转移.     

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。