Abstract 2486: Dissecting tumor-immune interaction in response and resistance to immune checkpoint blockade in metastatic melanoma

Abstract Background: Immune checkpoint blockade (ICB) has revolutionized the treatment and prognosis of various cancers, including melanoma. Nevertheless, intrinsic or acquired resistance is common, and the interactions between tumor-intrinsic features and the microenvironment underlying these resistances remain unclear for most patients. Methods: In this study, we developed a framework to analyze response and resistance, both intrinsic and acquired, via tumor-intrinsic programs, immune features, and tumor-stromal-immune interactions in a standardized, uniformly processed, and deeply clinically annotated cohort of metastatic melanoma patients (n=61) treated with ICB as part of the NCI funded human tumor atlas network (HTAN) initiative. From the same tumor samples (pre-treatment (n=33) and post-progression (n=28)), we conducted bulk whole-exome sequencing (WES), single-nucleus RNA sequencing, and for a subset of the samples high-resolution spatial imaging (including protein mIHC, CODEX, and transcriptomics MERFISH). Standardized processing and data pipelines allowed for integration of genomic, transcriptomic, and spatial features to elucidate shared tumor and microenvironmental states and their relationships with resistance. Results: Our preliminary analysis on a subset of 28 samples identified an enrichment of B cells, plasma cells, and T follicular helper-like cells in the tumor microenvironment (TME) of patients sensitive to treatment. The TME of non-responders was predominantly characterized by macrophage/monocyte cell populations. Post-treatment responder samples showed an enrichment of CD4+ T cells. Genomic heterogeneity, assessed through WES, was confirmed as a feature of intrinsic resistance across different ICB treatment settings, while ploidy was associated with treatment response in pre-treatment, ipilimumab-naïve patients treated with PD-1 inhibitors. Comparing the immune compartments of samples with high and low heterogeneity revealed NK cell enrichment in samples with a high proportion of subclonal mutations. Conclusions and Future Directions: Overall, our work provides a high-resolution understanding of the tumor-stromal-immune interaction in metastatic melanoma, shedding light on the factors contributing to therapy response and resistance, and contributing a repository of data from deeply clinically annotated, multimodally characterized and uniformly processed patient samples. Ongoing spatial analysis will further enhance our understanding of these compartments at a spatial level. The results of our study have the potential to guide more personalized and effective treatment strategies for metastatic melanoma in the future. Citation Format: Giuseppe Tarantino, Yiwen He, Priyanka Solanky, Aaron Thorner, Tyler Aprati, Ryan Sullivan, Emily Robitschek, Timothy Blosser, Xiaowei Zhuang, Xiaowei Zhuang, Elliot Boblitt, Allison Frangieh, Marta Holovatska, Aleigha Lawless, Michael Manos, Kathleen Pfaff, Karla Helvie, Tatyana Sharova, Dennie Frederick, James Liam Fahey, Diego Villamarin, Sami Farhi, Scott Rodig, Bruce Johnson, Alex K. Shalek, Eliezer Van Allen, Stephen Hodi, Genevieve M. Boland, David Liu. Dissecting tumor-immune interaction in response and resistance to immune checkpoint blockade in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2486.