Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity.
Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity.
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DOI：
10.3389/fimmu.2018.00887
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发表时间：
2018
影响因子：
7.3
通讯作者：
Chouaib S
中科院分区：
文献类型：
--
作者：
Janji B;Berchem G;Chouaib S
癌细胞在肿瘤微环境中进化，肿瘤微环境现在已被公认为肿瘤的组成部分，并且是癌细胞适应和对抗癌疗法的抗性的决定性参与者。尽管在过去的二十年里，我们对肿瘤微环境在癌症发展中的作用的理解取得了显着和相当快的进展，但其对癌症耐药性的确切贡献仍然是分散的。这主要与“肿瘤生态系统”的复杂性和构成肿瘤微环境的基质细胞类型的多样性有关。新出现的数据表明，几个因素，如缺氧应激，激活了过多的抵抗机制，包括自噬，在肿瘤细胞。肿瘤微环境中缺氧诱导的自噬也激活了几种肿瘤逃逸机制，这些机制有效地抵消了自然杀伤细胞和细胞毒性T淋巴细胞介导的抗肿瘤免疫应答。因此，旨在靶向癌细胞中的自噬的策略与其他治疗策略相结合，激发了人们对克服免疫耐受和促进肿瘤消退的极大兴趣。然而，自噬抑制剂在临床上的应用仍然受到许多障碍的阻碍。首先，目前自噬的药理学抑制剂缺乏选择性，很难明确说明其在癌症中的有效作用。其次，自噬也被描述为肿瘤细胞中参与向T细胞呈递抗原的重要机制。第三，有间接证据表明，一些先天免疫细胞中的自噬激活可能支持这些细胞的成熟，并且是其抗肿瘤活性所必需的。在这篇综述中，我们将讨论这些方面，并讨论我们目前的知识的好处和靶向自噬在抗肿瘤免疫的背景下的缺点。我们认为，重要的是要解决这些问题，以预测自噬抑制剂与免疫疗法在临床环境中的组合使用。
Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is important to resolve these issues to predict the use of autophagy inhibitors in combination with immunotherapies in clinical settings.