恶性肿瘤缺氧酸性微环境对免疫治疗影响机制的研究进展

Mechanisms by which tumor hypoxic and acidic microenvironments affect immunotherapy

近年来,以免疫检查点阻断单克隆抗体和抗原受体T细胞免疫疗法细胞治疗为代表的免疫疗法在治疗恶性肿瘤方面取得突破性进展.然而,肿瘤通过各种不同的机制逃避免疫系统的识别和杀伤,导致免疫治疗效果仍不理想.由癌细胞、血管、淋巴、成纤维细胞、炎症细胞以及多种细胞外基质有机构成的肿瘤组织微环境不仅支持癌细胞的生长和转移,也影响免疫细胞识别和杀伤癌细胞以及迁移的功能,调控免疫效应分子的活化,从而影响免疫治疗的效果.实体肿瘤内异常血管网络和快速生长的癌细胞对氧过量需求导致肿瘤组织缺氧,并加剧由于癌细胞异常代谢导致肿瘤组织的酸性微环境.缺氧酸性微环境是肿瘤微环境最重要的组成部分,癌细胞适应和利用这些微环境,导致基因变异的多样性和不稳定性,激活多种信号通路和生存因子,造成肿瘤对包括免疫治疗在内的多种治疗方法的耐受和抵抗.本文针对近年来肿瘤缺氧酸性微环境对免疫治疗影响机制的研究进展进行述评,希望给从事癌症微环境和免疫治疗的临床基础科研人员提供新的思路.

Cancer immunotherapy has become one of the areas in which major medical breakthroughs are being witnessed. The recent promising progress in activating therapeutic anti-tumor immunity, such as checkpoint blockade and chimeric antigen receptor T-cell immuno therapy therapy, has made us closer to, but there is still a long way to reach, the final goal in the battle against cancer, since cancer cells utilize different mechanisms to escape from immune attack, leading to limited efficacy of immunotherapies in treating malignant tumors. Tumor tissues consist of cancer cells, blood vessels, lymphatic capillaries, fibroblasts, inflammatory cells and various types of extracellular matrixes, which compose tumor microenvironments. Tumor microenvironments not only support the growth and metastasis of cancer cells, but also affect the recognition and killing of cancer cells by immune cells and their ability to migrate and regulate the activation of effector molecules, thus influencing the therapeutic effects of immunotherapies. Tumor hypoxic microenvironments are caused by abnormal blood supply networks and outweighing demands of oxygen by fast dividing cancer cells. Hypoxia can also, together with abnormal metabolism of cancer cells, lead to sequential tumor acidic microenvironments. Hypoxic and acidic microenvironments are frequentlyobserved in almost all solid tumors, and adapted and exploited by cancer cells for their survival and invasion. Hypoxic and acidic microenvironments can also result in the diversity and instability of gene mutations and the activation of cellular signaling pathways and survival factors, and have been regarded as one of the major causes of the resistance to various therapies including immunotherapy. The present article summarizes the recent progress in the understanding of the mechanisms by which tumor hypoxic and acidic microenvironments influence immunotherapy, and analyzes the potential strategies for coping with these obstacles to combating cancer. We hope it can provide some new clues for clinicians and scientists engaged in the research areas of tumor microenvironments and immunotherapy.