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April 3rd, 2025
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1Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway 2Department of Pathology, Oslo University Hospital-Rikshospitalet, Os
cancer biology
biorxiv

Single cell spatial transcriptomics identifies coordinated cellular programs that are associated with good prognosis in microsatellite stable colorectal cancer

Karlsen, V. T.Open in Google Scholar•Majid, U.Open in Google Scholar•Lindholm, H. T.Open in Google Scholar•Umu, S. U.Open in Google Scholar•Vander-Elst, K. R.Open in Google Scholar•Beitnes, A.-C. R.Open in Google Scholar•Merok, M. A.Open in Google Scholar•Hagen, K. T.Open in Google Scholar•Nilsen, H. R.Open in Google Scholar•Yaqub, S.Open in Google Scholaret al.

It has been reported that microsatellite instable (MSI) tumors in colorectal cancer (CRC) exhibit stronger anti-tumor immune responses than microsatellite stable (MSS) tumors. Using a simple classification system we recently showed that MSS tumors with both high numbers of tumor-associated macrophages (TAMs) and T cells had good prognosis, whereas high numbers of TAMs and low numbers of T cells had by far the worst prognosis. To uncover the underlying mechanisms for this difference we created a comprehensive spatial transcriptomic atlas of the cellular and molecular landscape in CRC. Analyzing scRNA-seq data from 185 CRC patients we found that TAMs, T cells, tumor, stromal, and endothelial cells in MSS tumors with high numbers of CD8 T cells and TAMs (CD8hiTAMhi) and CD8lowTAMhi MSS tumors were enriched for pathways associated with anti-tumor and pro-tumor responses, respectively. In CD8hiTAMhi tumors, TAMs expressed an IFN-induced phenotype (e.g. GBP1, CXCL9, CXCL10, IFITM3) and high infiltration of GBP1+ TAMs was associated with better overall survival in CRC patients with MSS tumors (n=941). High resolution spatial transcriptomics (Visium HD) revealed that GBP1+ TAMs clustered with CXCL13+IFNG+PDCD1+ CD8 T cells in tumoral niches, suggesting that GBP1+ TAMs were involved in recruitment and activation of tumor-reactive CD8 T cells. Together, we showed that a simple classification system based on CD8 T cell and TAM densities uncovered coordinated cellular programs across cell types in the tumor microenvironment of MSS tumors that were strongly associated with prognosis. This classification system may aid clinicians to better stratify CRC patients for personalized treatment.

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