Campbell and Amouzgar et al. aggregated and harmonized whole exome sequencing (WES) and RNAseq data from biopsies across seven checkpoint blockade-treated clinical cohorts comprising 514 patients with melanoma. Harmonization enhanced the statistical power to correlate genomic and expression-based features with clinical responses to different ICB regimens. Using this resource, the team found that in anti-CTLA-4-experienced (but not anti-CTLA-4 naive) patients, immune cell signatures were enhanced, and inflammatory signatures, altered cell cycle processes, and tumor mutation burdens (TMB) were associated with response to anti-PD-1.
Contributed by Lauren Hitchings
ABSTRACT: Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: katiecampbell@mednet.ucla.edu. (
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: katiecampbell@mednet.ucla.edu. (2) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (3) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (4) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (5) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. (6) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (7) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (8) Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. (9) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA. (10) Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Bristol Myers Squibb Corp., Princeton, NJ 08540, USA. (13) Bristol Myers Squibb Corp., Princeton, NJ 08540, USA. (14) Bristol Myers Squibb Corp., Princeton, NJ 08540, USA. (15) Bristol Myers Squibb Corp., Princeton, NJ 08540, USA. (16) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (17) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (18) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (19) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90024, USA. Electronic address: aribas@mednet.ucla.edu.
