Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
Centre Hospitalier du Luxembourg, Department of Hemato-Oncology, Luxembourg City, Luxembourg.
Front Immunol. 2018 Apr 25;9:887. doi: 10.3389/fimmu.2018.00887. eCollection 2018.
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.
癌细胞在肿瘤微环境中进化，现在已经明确，肿瘤微环境是肿瘤的一个组成部分，也是决定癌细胞适应和抵抗抗癌疗法的关键因素。尽管在过去的二十年中，我们对肿瘤微环境在癌症发展中的作用的理解取得了显著而相当迅速的进展，但它对癌症耐药的确切贡献仍然是零散的。这主要与“肿瘤生态系统”的复杂性以及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，一些因素，如缺氧应激，激活了大量的耐药机制，包括自噬。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反应。因此，靶向肿瘤细胞自噬与其他治疗策略相结合的策略激发了人们极大的兴趣，以克服免疫耐受并促进肿瘤消退。然而，许多障碍仍然阻碍了自噬抑制剂在临床上的应用。首先，目前自噬药理学抑制剂缺乏选择性，使得很难清楚地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一种重要的机制，参与抗原呈递给 T 细胞。第三，有间接证据表明，某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，并讨论我们目前对靶向自噬在抗肿瘤免疫中的益处和缺点的认识。我们认为，解决这些问题对于预测自噬抑制剂与免疫疗法联合在临床中的应用非常重要。
