Autophagy protects tumors from T cells
Tumors evade antitumor T cells by various mechanisms. Young et al. used a CRISPR screen to identify that TNFα and autophagy play a role in T cell–mediated killing of tumor cells. Pharmacologic or genetic (CRISPR knockout of Rb1cc1) inhibition of autophagy in tumor cells increased TNFα-mediated T cell killing of tumor cells. Rb1cc1 knockout in tumor cells improved the efficacy of immune checkpoint blockade in a mouse tumor model. However, CRISPR knockout of the TNFα receptor in tumor cells partially abrogated the improved efficacy of immune checkpoint blockade in the absence of Rb1cc1. Thus, autophagy inhibition may improve T cell–mediated immunotherapies in patients with cancer.
Abstract
Although T cell checkpoint inhibitors have transformed the treatment of cancer, the molecular determinants of tumor cell sensitivity to T cell–mediated killing need further elucidation. Here, we describe a mouse genome–scale CRISPR knockout screen that identifies tumor cell TNFα signaling as an important component of T cell–induced apoptosis, with NF-κB signaling and autophagy as major protective mechanisms. Knockout of individual autophagy genes sensitized tumor cells to killing by T cells that were activated via specific TCR or by a CD3 bispecific antibody. Conversely, inhibition of mTOR signaling, which results in increased autophagic activity, protected tumor cells from T cell killing. Autophagy functions at a relatively early step in the TNFα signaling pathway, limiting FADD-dependent caspase-8 activation. Genetic inactivation of tumor cell autophagy enhanced the efficacy of immune checkpoint blockade in mouse tumor models. Thus, targeting the protective autophagy pathway might sensitize tumors to T cell–engaging immunotherapies in the clinic.