Data from Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell–Secreted Cytokines

Abstract

<div>Abstract<p>Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)–bound peptides, but this selection pressure favors outgrowth of MHC-I–deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell–mediated killing of MHC-I–deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of <i>Rnf31</i> (TNF signaling) and <i>Atg5</i> (autophagy) sensitized MHC-I–deficient tumor cells to apoptosis by T cell–derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I–deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ-and TNFα-producing T cells. Tumors with a substantial population of MHC-I–deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacologic approaches.</p>Significance:<p>Tumor heterogeneity is a major barrier to immunotherapy. We show that MHC-I–deficient tumor cells are forced into apoptosis by T cell–derived cytokines when TNF signaling and autophagy pathways are targeted. This approach enables T cell–mediated elimination of tumors with a substantial population of resistant, MHC-I–deficient tumor cells.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-5-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 1027</a></i></p></div>