Emerging Role of Hypoxia-Induced Autophagy in Cancer Immunotherapy

Cytotoxic T-lymphocytes (CTLs) are central effectors to eliminate cancer cells in an antigen- and cell contact-dependent manner, and induce long-lasting tumor regression. However, CTLs often fail to eradicate established tumors, likely as a consequence of failed infiltration and/or a locally immunosuppressive and metabolically perturbed tumor microenvironment. In fact, tumor cell growth in vivo is not only influenced by CTL-tumor cell recognition and tumor susceptibility to cell-mediated death, but also by the complex and highly dynamic tumor microenvironment, providing important clues to tumor development and progression. Besides the development of cancer vaccines, recent years have also seen the emergence of novel cancer immunotherapies based on our increasing knowledge of T cell molecules that regulate T cell responses. This has resulted in the development of several monoclonal antibody (mAb)-based therapies, such as anti-CTLA-4 or anti-PD-1, which have recently shown clinical benefits in several cancers. Accumulating experimental and clinical evidence indicates that multiple mechanisms suppressing the antitumor immune functions are directly developed in the tumor microenvironment. Recently, attention has focused on the mechanisms by which tumor microenvironmental hypoxia alters tumor transcriptional profiles to modulate glycolysis, proliferation, survival, and invasion. This chapter will summarize the recent progress in understanding the influence of tumor microenvironment, in particular hypoxia-induced autophagy, on the tumor survival mechanisms, and subsequently the quality of the antitumor response.