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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., (© 2023. The Author(s).)

Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMB high and TCB high or BCB high have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3 . Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes., Competing Interests: S.S.F., M.S.-F., and N.H. are inventors on provisional patent application No.62/866,261 related to methods for predicting outcomes of checkpoint inhibition described in this manuscript. I.L. is a consultant for PACT Pharma Inc. O.G.S. is an employee at Gritstone Oncology. J.A.W. is an inventor on a US patent application (PCT/US17/53.717) “Methods for enhancing immune checkpoint blockade therapy by modulating the microbiome” and a patent “Targeting B Cells To Enhance Response To Immune Checkpoint Blockade” UTSC.P1412US.P1 - MDA19-023. J.A.W. reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, and Bristol-Myers Squibb (BMS) and serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, BMS, Merck, and Ella Therapeutics. K.T.F. serves on the Board of Directors of Clovis Oncology, Strata Oncology, Kinnate, Checkmate Pharmaceuticals, and Scorpion; Scientific Advisory Boards of PIC Therapeutics, Apricity, Tvardi, xCures, Monopteros, and Vibliome; consultant to Lilly, Takeda, and Boston Biomedical; and research funding from Novartis and Sanofi. R.J.S. serves as a consultant/advisory board member for Asana Biosciences, AstraZeneca, BMS, Eisai, Lovane, Merck, Novartis, OncoSec, Pfizer, and Replimune and receives research support from Merck. G.M.B. has served on SAB and on the steering committee for Nektar Therapeutics. She has SRAs with Olink proteomics and Palleon Pharmaceuticals and served on SAB and as a speaker for Novartis. M.M. is the scientific advisory board chair of OrigiMed, is an inventor of a patent licensed to LabCorp for EGFR mutation diagnosis, and receives research funding from Bayer, Janssen, Novo, and Ono. G.G. receives research funds from IBM and Pharmacyclics, is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, MSIdetect, POLYSOLVER, and TensorQTL, and is a founder and consultant and has privately held equity in Scorpion Therapeutics. N.H. holds equity in BioNTech and is an equity holder and advisor for Danger Bio/Related Sciences., (© 2021 The Author(s).)