Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer

Ravi A*, Hellmann MD*, Arniella MB*, Holton M, Freeman SS, Naranbhai V, Stewart C, Leshchiner I, Kim J, Akiyama Y, Griffin AT, Vokes NI, Sakhi M, Kamesan V, Rizvi H, Ricciuti B, Forde PM, Anagnostou V, Riess JW, Gibbons DL, Pennell NA, Velcheti V, Digumarthy SR, Mino-Kenudson M, Califano A, Heymach JV, Herbst RS, Brahmer JR, Schalper KA, Velculescu VE, Henick BS, Rizvi N, Jänne PA, Awad MM, Chow A, Greenbaum BD, Luksza M, Shaw AT, Wolchok J, Hacohen N#^, Getz G#^, Gainor JF#^
Nature Genetics (2023)


Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

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