Abstract Alaska Native peoples experience high colorectal cancer (CRC) incidence and mortality rates, which Alaska tribal health organizations are working to address. To reduce the high rates, it is important to understand the biological mechanisms that drive risk and survival outcomes. The tumor microenvironment (TME) comprises diverse cell types, including cancer, stromal, and immune cells, whose composition and spatial organization may impact prognosis and disease progression. We performed spatial proteomics profiling on tissue microarrays from 97 Alaska Native patients with CRC using Akoya Biosciences’ PhenoCycler-Fusion system. We included 35 patients who died of CRC and 62 matched patients who did not die of CRC and lived at least as long as the patient they were matched to. Patients were matched on age at diagnosis, sex, tumor site, tumor stage, and year at diagnosis. We classified 2.90 million cells into 16 distinct cell types. We quantified immune and stromal cells as proportions of non-epithelial cells and epithelial cells as proportions of total cells. For spatial analysis, we identified eight cellular neighborhoods with distinct local cell composition and calculated spatial proximities between different cell types. We performed multivariable-adjusted logistic regression with generalized estimating equations to investigate associations of CRC-specific death with proportions of cell types and spatial proximities. We estimated odds ratios (OR) with 95% confidence intervals (CI) and calculated the false discovery rate (FDR) to account for multiple comparison using the Benjamin-Hochberg method. We found that higher proportions of stromal cells (OR for doubling of proportion=2.29, 95%CI=1.00-5.26) and higher proportion of M2 macrophages at the tumor center (OR=2.90, 95%CI=1.14-8.22) were associated with increased risks of CRC-specific death among 76 patients with microsatellite stable (MSS) tumors. We observed higher proportions of podoplanin (PDPN)-expressing stromal cells (OR=2.97 for doubling of proportion, 95%CI=1.28-7.08) and M1 macrophages (OR=2.42, 95%CI=1.05-5.69) within cellular neighborhoods predominantly composed of tumor epithelial cells among patients with CRC deaths compared to survivors, although these associations did not remain significant at FDR 0.05. Additionally, we observed that colocalization of PDPN-expressing stromal cells with CD8+ T cells, and colocalization of antigen-presenting cells with plasma cells, was associated with increased risk of CRC-specific death. In contrast, colocalization of B cells with stromal cells was associated with decreased risk (adjusted P=0.04 for all associations). Those associations remained significant among patients with MSS (adjusted P=0.03). This is the first study focusing on the TME cellular landscape among Alaska Native patients with CRC. Our results highlight the prognostic relevance of cellular composition and spatial organization within the TME, suggesting specific stromal and immune cell interactions as potential biomarkers for CRC outcomes. Citation Format: Hang Yin, Diana Redwood, Kimberly Smythe, Kristin L. Robinson, Daniel Jones, McGarry Houghton, Kevin C. Barry, Amanda L. Koehne, Elizabeth Donato, Cecilia Yeung, Minggang Lin, James J. Tiesinga, Tabitha A. Harrison, Sushma S. Thomas, Li Hsu, Jane C. Figueiredo, Li Li, Christopher I. Li, Ulrike Peters, Jeroen R. Huyghe. Spatial-resolved single-cell analysis of the tumor microenvironment in Alaska Native colorectal cancer patients reveals novel biomarkers for prognosis abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A087.
Yin et al. (Thu,) studied this question.