1245 Spatial distribution and abundance of tumor cells, T cells and macrophages correlate with recurrence of stage II and III melanoma

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Background Melanoma progression can be controlled by the immune system, but predicting patient outcomes remains challenging. Understanding tumor immune micro-environment architecture could inform and lead to novel therapies and biomarkers. Tumor-infiltrating lymphocytes (TILs) predict sentinel lymph node status and patient survival in cutaneous melanoma, but quantifying TILs is challenging. Besides high lymphocyte density defining a ‘hot’ tumor immune micro-environment, the spatial positioning of cells within the tumor bed also contains important information.1–3 Here, we test whether metrics quantifying the spatial distribution of immune cells correlate with recurrence-free survival (RFS). Methods Quantitative multiplex immunofluorescence (QmIF) was performed on 92 patients. Three types of cells were quantified: CD8+ T cells, CD68+ macrophages, and SOX10+ tumor cells. Cell proportions were calculated by normalizing the total count of each cell type by the sum of all three cell types. Spatial metrics were evaluated using count-in-radius (CIR) and nearest neighbor distance (NN). CIR quantifies the number of specific cell types (e.g. CD8 or CD68) within a circle (of radii 10, 15, 20, or 100µm) centered on each immune cell (figure 1A). NN measures the mean distance from each immune cell to the nearest k (1, 5, or 20) neighboring cells (figure 1B). To determine the correlation with patient outcome, we performed a multivariate Cox model analysis looking at recurrence-free survival (RFS). Results Of the 92 melanoma patients, 25 experienced recurrence, while 67 remained recurrence-free. Tumor cell proportion (HR=1.52, 95% CI=1.13–2.03, p=0.005) and CD8 cell proportion (HR=0.49, 95% CI=0.30–0.81, p=0.005) were significant predictors (table 1). Higher tumor cell proportion and lower CD8 cell proportion were linked to poor prognosis and increased recurrence risk. CIR analysis for CD8 cells (centered on CD8 cells, HR=0.86, 95% CI=0.77–0.97, p=0.010; centered on CD68 cells, HR=0.80, 95% CI=0.67–0.94, p=0.009) showed that fewer clustered CD8 cells correlated with higher recurrence risk. Increased CD8-CD8 cell distance (HR=1.04, 95% CI=1.02–1.07, p<0.001), CD8-CD68 cell distance (HR=1.04, 95% CI=1.02–1.07, p=0.001), and CD68-CD8 cell distance (HR=1.05, 95% CI=1.02–1.07, p<0.001) were significant (table 1), indicating that greater distance between these cells increased recurrence likelihood. Conclusions 1) The spatial distribution of immune cells is a prognostic marker for RFS in melanoma, with the distance between CD8+ T cells and CD68+ macrophages significantly associated with recurrence. 2) Lower CD8+ T cell abundance correlates with higher recurrence risk, highlighting their critical role in combating melanoma. These findings suggest that immune cell distribution and abundance in the tumor microenvironment hold promise as prognostic indicators for melanoma recurrence. References Gartrell RD, et al. Quantitative multiplex immunofluorescence (qmIF) and genomic evaluation of tumor microenvironment (TME) to identify candidate biomarkers in stage II/III melanoma. American Society of Clinical Oncology, 2018. Gartrell RD, et al. Quantitative compositional and spatial analysis of tumor microenvironment (TME) in primary melanoma. Cancer Res. 2018;78:2091–2091. Rizk EM, et al. Abstract B11: Prognostic biomarkers in stage II-III melanoma. Cancer Res. 2020;80:B11-B11.

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