4.7 Article

Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade

Journal

CANCER DISCOVERY
Volume 10, Issue 9, Pages 1296-1311

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-1416

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Funding

  1. Melanoma Research Foundation
  2. O'Connor-Macgregor Fund for Melanoma Research
  3. Stand Up To Cancer (SU2C) Innovative Research Grant [SU2C-AACR-IRG 16-17]
  4. BroadNext10
  5. NIH [R01CA227388]
  6. Damon Runyon Cancer Foundation Physician Scientist Training Grant
  7. Conquer Cancer Foundation
  8. Society for Immunotherapy of Cancer-Bristol-Myers Squibb Postdoctoral Cancer Immunotherapy Translational Fellowship
  9. NCI [P50CA101942]
  10. Damon Runyon-Rachleff Innovator Award

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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.

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