A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing

TLDR

Immune checkpoint inhibitors produce durable tumor regressions in some patients, but not all, and understanding the mechanisms of tumor sensitivity could broaden patient benefit. The study examined genomic features of metastatic renal cell carcinoma tumors treated with immune checkpoint inhibitors. Inactivation of the SWI/SNF chromatin remodeling complex, including PBRM1 mutations, increases tumor sensitivity to T cell–mediated killing, enhances interferon‑γ responsiveness, and promotes antitumor immunity, thereby improving response to immune checkpoint inhibitors. References include Pan et al., Miao et al., and Science issue pages 770, 801, and 745.

Abstract

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745