Hypoxia-induced autophagy in tumor cells: a key target for improving cancer immunotherapy.

Cancer was initially thought to be just a disease of cells with deregulated gene expression. It may be more accurate to consider also cancer as a disease of the microenvironment. It is now well documented that the tumor microenvironment plays a determinant role in cancer cell adaptation and resistance to therapies. In particular, hypoxia has been described to play a central role in activating multiple overlapping adaptive mechanisms leading to the emergence of resistant tumor cells able to outmaneuver an effective immune response and escape from immune cell killing. Despite the remarkable and fairly rapid progress over the past two decades regarding the role of the microenvironment in cancer biology and treatment, our understanding of its actual contribution to cancer resistance is still poor and fragmented. Moreover, the microenvironment is now considered to be of critical importance during the initiation and progression of carcinogenesis. By playing a key role in shaping and remodeling stroma reactivity and reprogramming phenotypic and functional plasticity, the tumor microenvironment represents therefore an important hallmark of cancer. A challenge for immunologists is to better understand tumor plasticity and immune-resistant tumor cell variants, which appear to be the greatest impediment to successful immunotherapy.
In this context autophagy has recently emerged as a new player in regulating the anti-tumor immune response in hostile tumor microenvironment. In this review, we summarize recent data describing how autophagy activation under hypoxia impairs the anti-tumor immune response. It is our belief thatautophagy may represent a conceptual realm for new immunotherapeutic strategies aiming to block immune escape and therefore providing rational approach to future tumor immunotherapy design.