Dual effect of autophagy in the regulation of cell-mediated cytotoxicity

The immune system is a potent defense mechanism regulating tumor development and progression. The ultimate goal of cancer immunotherapy is to eradicate malignant cells through the cytotoxic machinery of immune cells such as cytotoxic T cells (CTLs) and Natural killer (NK) cells. However, the killing potential of these cells is often dampened by the tumor microenvironment (TME) known for its complexity and hostility. Blockers of checkpoint inhibitors have yielded impressive clinical results and have recently been approved for use in a wide variety of cancers. Although the advent of these new immunotherapy approaches has improved the survival of many patients with advanced malignancies, the high prevalence of non-responders, also provides a strong reminder that we possess only a partial understanding of the events underlying the immune resistance of tumors. Several factors within the tumor microenvironment are involved in sculpting, regulating stroma and tumor reactivity through the regulation of tumor resistance, immune suppression and tumor heterogeneity and plasticity. In this chapter we will discuss how autophagy shapes the quality of adaptive and natural cell cytotoxic response and survival pathways and therefore may impact the clinical benefit of immune cell-based therapies. In addition, this review will critically assess whether autophagy confers cancer cell susceptibility to cell death. Thus, a better understanding for eliciting the dual effect of autophagy is needed to integrate its induction or targeting in the future immunotherapy approaches.