Autophagy protects tumors from T cell–mediated cytotoxicity via inhibition of TNFα-induced apoptosis
Tara M. Young, Claudia Reyes, Elizabeth Pasnikowski, Carla Castanaro, Chung Wong, Corinne E. Decker, Joyce Chiu, Hang Song, Yi Wei, Yu Bai, Brian Zambrowicz, Gavin Thurston, Christopher Daly
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.