Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is…

• CC
  Conquer Cancer Foundation
• M
  Merck
• SF
  Starr Foundation
• PS
  Pershing Square Foundation
• SA
  Swim Across America
• NI
  National Institutes of Health

  Awards: K08 DE024774, 5P30 CA008748-50, R01 DE027738, 1R01CA205426, CA009685
• SU
  Stand Up To Cancer

  Award: SU2C-AACR-DT22-17