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Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation

Van Allen, Golay, Liu, and colleagues genomically profiled tumor and germline samples from a patient with activating JAK3 variants who achieved long-term clinical benefit from anti–PD-L1 therapy, suggesting that alterations in JAK signaling may be immunogenomic modulators of response to PD-L1 immunotherapy. PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti–PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. Cancer Immunol Res; 3(8); 855–63. ©2015 AACR.