Abstract A070: Immune and metabolic architecture of TIME in metastatic acral melanoma patients treated with checkpoint inhibitors

Abstract The Immune Checkpoint Inhibitors (ICIs) have significantly changed treatment approaches for patients with various cancers, including melanoma, in advanced and/or adjuvant settings. Acral melanomas are rare but aggressive clinical subtype of melanomas and there is an urgent need to improve care for acral melanomas aimed at the treatment with ICIs. While biomarker studies and drug discoveries in cutaneous melanoma have achieved substantial progress, little is known about either what are the prognostic markers for acral melanomas and how to predict response to ICI treatment modalities. Here, we target to understand prognostic significance of Tumor Immune Micro Environment (TIME) characteristics and progression of acral melanomas as well as the predictive factors for the ICI-treatment options, with a specific focus on complex immune-biology between white and non-white patients with acral melanomas. In our current study, we hypothesized that innate inflammatory enzymes and their mediators in acral melanoma TIME causes “immune exclusion” by altering the tissue structure that could be otherwise “immune inflamed” and incline the tumor responsiveness. To understand the complexity of the TIME in these patients, we visualized this highly complex cellular structure and studied it in its intact form for many protein biomarkers. We performed a retrospective analysis of 40 tumor tissue samples from patients with advanced or metastatic acral melanoma, treated with anti-CTLA4 or anti-PD1 immunotherapy to characterize the immune signatures and perform and quantify immune cell profiling in pre-treatment and on-treatment tumor tissue samples. For detailed immunophenotyping of TIME, we used cycling IHC (by Lunaphore-Comet) for 40 individual cell surface and intracellular markers per cell, as well as additional structural and functional markers. We further performed inflammatory markers by multiplex IHC (by Opal system) to align our inflammatory cores with immune cell neighborhoods. We have also performed imaging of metabolites, glycans, and peptides MALDI-TOF mass spectrometer in the same cohort and encouraged by our preliminary results on differential characteristics on tumor areas with various immune infiltration, such as no immune cells, versus peripheral or intratumoral localizations. Our initial analyses revealed that the differences in immune cell distribution inside tumor areas (peri- versus intra-tumoral areas), as well as patient ethnicities (Hispanic or Latino versus non-Hispanic white), specifically on NK cells and macrophage subtypes, which supports our original hypothesis on differential and complex immune-biology on white and non-white patients with acral melanomas. Our ongoing proteomics and metabolomics analyses of TIME in this unique cohort of acral melanomas, as one of the rarest and relatively under explored group of patients, will further guide us in stratifying patient selections and personalize the future treatment decisions. Citation Format: Suhendan Ekmekcioglu, Kaysia Ludford, SungNam Cho, Salah Eddine-Bentebibel, Akshay V Basi, Reham Abdel-Wahab, Khalida M Wani, Noha Abdel-Wahab, Jared K Burks, Adi Diab. Immune and metabolic architecture of TIME in metastatic acral melanoma patients treated with checkpoint inhibitors [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A070.