Abstract 3271: Multiomic meta-analysis of differential response to PD-1 and CTLA-4 blockade in metastatic melanoma

Abstract Background: While CTLA-4 and PD-1 immune-checkpoint blockade (ICB) have revolutionized melanoma treatment, these treatments have different mechanisms, response rates, and toxicities. Differential predictors of response are poorly characterized. Combination ICB has the highest response rates but also much higher toxicity, and which patients to treat with single agent vs. combination ICB is controversial. In this study, we set out to understand the differential biology of anti-CTLA-4 and anti-PD-1 by integrating transcriptomic and clinical characterization from large cohorts of patients with metastatic melanoma treated with anti-CTLA-4, anti-PD-1, or combination blockade. Methods: We performed a standardized meta-analysis of all available cohorts of ICB-treated (anti-PD-1 alone, anti-CTLA-4 alone, and combination) melanoma patients with sequencing of pretreatment tumor and clinical annotations (n=572; 268 evaluated post quality-control filtering, cutaneous). Raw data in the form of FASTQs were obtained for all cohorts, and data were reprocessed using standardized pipelines. Immune infiltrate was characterized using single-sample gene set enrichment analysis (ssGSEA) scores from 18 immune cell type signatures, and GSEA was performed on differentially expressed genes between responders and non-responders for each treatment cohort accounting for differences in immune infiltrate. To dissect the cell types and drivers of nominated signatures, we analyzed scRNAseq from a separate cohort of pretreatment metastatic melanoma. Results: We found that immune infiltrate was strongly predictive of response to combination blockade (OR=6.16, p<0.05) but had a weaker signal in the monotherapy context (anti-PD-1 OR=1.42, n.s.; anti-CTLA-4 OR=1.10, n.s.). Among samples with a high degree of immune-infiltrate treated with either anti-CTLA-4 and anti-PD-1, non-responders were enriched in hypoxia (avg. NES=-1.38, FDR<0.05) and epithelial-mesenchymal transition (avg. NES=-2.32, FDR<0.05) gene signatures. Preliminary analysis of the single cell cohort shows a specific population of myeloid cells (MW p<0.05) and exhausted CD8+ T cells (MW p<0.05) increased in pretreatment hypoxic tumors. Conclusion: High rates of response to combination in patients with high levels of immune infiltrate suggests that immune high patients may differentially benefit from combination blockade. Identifying features of non-responding patients stratified by immune infiltrate can lead to new biological insights into ICB. Citation Format: Amy Y. Huang, Natalie Vokes, Cora Ricker, Tyler Aprati, Emily Robitschek, Jiekun Yang, Li-Lun Ho, Kyriakitsa Galani, Kelly P. Burke, Giuseppe Tarantino, Jiajia Chen, Arlene H. Sharpe, Eliezer M. Van Allen, Manolis Kellis, Genevieve M. Boland, David Liu. Multiomic meta-analysis of differential response to PD-1 and CTLA-4 blockade in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3271.