Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that…

• NS
  National Science Foundation
• CR
  Cancer Research Institute
• MR
  Melanoma Research Alliance
• DM
  Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
• BI
  Broad Institute
• NI
  National Institutes of Health
• SU
  Stand Up To Cancer
• NH
  National Human Genome Research Institute

  Award: 5U54HG003067
• NC
  National Cancer Institute