Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma

• Published in: Cancer cell Vol. 41; no. 4; pp. 791 - 806.e4
• Main Authors: Campbell, Katie M., Amouzgar, Meelad, Pfeiffer, Shannon M., Howes, Timothy R., Medina, Egmidio, Travers, Michael, Steiner, Gabriela, Weber, Jeffrey S., Wolchok, Jedd D., Larkin, James, Hodi, F. Stephen, Boffo, Silvia, Salvador, Lisa, Tenney, Daniel, Tang, Tracy, Thompson, Marshall A., Spencer, Christine N., Wells, Daniel K., Ribas, Antoni
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2023
• Subjects: Biomarkers, Tumor; CTLA-4 Antigen - genetics; Humans; immune checkpoint blockade; Immunotherapy; melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; meta-analysis; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Tumor Microenvironment; meta-analysis; melanoma; immunotherapy; immune checkpoint blockade
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.03.010

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. [Display omitted] •Harmonization of molecular and clinical annotation clarifies anti-PD-1 response patterns•Prior anti-CTLA-4 treatment modifies predictors of anti-PD-1 response in melanoma•Immune cell signature differences are enhanced in tumors with prior anti-CTLA-4 Campbell et al. aggregate genomics and transcriptomics data across melanoma datasets, harmonizing molecular and clinical annotation across samples. Immune cell gene expression patterns and tumor mutational burden, as predictors of anti-PD-1 response, are modified by whether the patient previously received anti-CTLA-4 therapy.