Primary Resistance to PD-1 Blockade Mediated by JAK½ Mutations

Primary Resistance to PD-1 Blockade Mediated by JAK½ Mutations |abstract

 Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted 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. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway. JAK½ loss-of-function alterations in TCGA confer adverse outcomes in patients. We propose that JAK½ loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.