UCLA

Blocking programmed death protein 1 (PD-1) negative immune receptor has produced remarkable progress in treating patients with advanced cancers, such as melanoma, lung, head and neck, kidney, bladder, Hodgkin’s disease, mismatch repair deficient colon cancer, liver and ovarian cancer with high mutational burden, etc. However, only subset of patients are benefitting from this therapy and substantial portion of patients have relapsed after long durable response. Therefore, it is critical to understand its resistance mechanisms to improve therapeutic efficacy and select right patients for checkpoint blockade immunotherapy. We have identified mutations associated with acquired resistance among 4 patients with advanced melanoma, including JAK1/2 that resulted in loss of adaptive programmed death protein ligand 1 (PD-L1). We reasoned that this could occur among patients with primary resistance. JAK1/2 inactivating mutations were found in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Two out of 48 human melanoma cell lines had JAK1/2 mutations led to loss of PD-L1 expression upon interferon gamma exposure mediated by disabled interferon gamma receptor signaling pathway. JAK1/2 loss-of-function alterations in TCGA confer adverse outcomes in patients. sh-RNA screening and chromatin immunoprecipitation approach on interferon signaling genes for selected melanoma cell lines revealed JAK1/2, STAT1/2/3 and IRF-1 are the key molecules involved in PD-L1 expression. RNA-seq analyses for tumors enriched with these genes were associated with clinical response to PD-1 blockade. Therefore, we propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary or acquired resistance to PD-1 blockade therapy.