A Set of Transcriptomic Changes Is Associated with Anti–PD-1 Resistance

Immune checkpoint blockade therapy targeting programmed cell death 1 (PD-1) has been efficacious against a number of cancer types, most prominently melanoma. However, patients with metastatic melanoma frequently exhibit innate resistance to anti–PD-1 therapy due to unknown molecular mechanisms. To identify the genomic determinants of anti–PD-1 response in patients with melanoma, Hugo, Zaretsky, and colleagues performed whole-exome sequencing (WES) and transcriptomic profiling of melanomas from patients treated with anti–PD-1 antibodies, a subset of whom had received prior MAPK inhibitor (MAPKi) treatment. WES of melanomas from responding and nonresponding patients showed that while high mutational load correlated with improved patient survival, there was no statistically significant association between high mutational load and response to anti–PD-1 therapy. Examination of individual mutations revealed that BRCA2 was more frequently mutated in anti–PD-1 responsive melanomas than in nonresponsive melanomas. Bioinformatic analysis of differentially enriched gene sets identified the innate anti–PD-1 resistance (IPRES) signature, which consisted of a set of co-enriched gene sets in nonresponders. A subset of these gene sets were found to be induced by MAPKi. The IPRES signature represented a group of 26 transcriptomic signatures associated with increased mesenchymal transition, inflammation, wound healing, and angiogenesis. Similarly, gene ontology analysis of differentially expressed genes showed that nonresponding tumors exhibited upregulation of genes associated with biological processes such as cell adhesion, extracellular matrix organization, response to wounding, and vasculature development. Examination of additional patient cohorts revealed that the IPRES signature was enriched more frequently in metastatic cutaneous melanoma compared to primary cutaneous melanoma and was enriched in subsets of other malignancies, such as lung adenocarcinoma and colon adenocarcinoma. Together, these results describe potential genomic determinants of response to anti–PD-1 therapy and suggest that treatment with anti–PD-1 or the combination of anti–PD-1 and MAPKi may be enhanced by targeting IPRES-related biological processes.

Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016;165:35–44.

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