Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade
- 4 May 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (9), 1296-1311
- https://doi.org/10.1158/2159-8290.CD-19-1416
Abstract
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.Other Versions
Funding Information
- Stand Up To Cancer (#SU2C-AACR-IRG 16-17)
- NIH (R01CA227388)
- NCI (P50CA101942)
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