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bioRxiv · 10.1101/2024.09.19.614002

A Paradoxical Tumor Antigen Specific Response in the Liver

Trehan, R. S.·Zhu, X. B.·Huang, P.·Wang, X.·Soliman, M.·Strepay, D.·Nur, A.·Kedei, N.·Arhin, M.·Ghabra, S.·Rodriguez Matos, F.·Benmebarek, M.-R.·Ma, C.·Korangy, F.·Greten, T. F.
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Abstract

Functional tumor-specific CD8+ T cells are essential for an effective anti-tumor immune response and the efficacy of immune checkpoint inhibitor therapy. In comparison to other organ sites, we found higher numbers of tumor-specific CD8+ T cells in primary, metastatic liver tumors in murine tumor models. Despite their abundance, CD8+ T cells in the liver displayed an exhausted phenotype. Depletion of CD8+ T cells showed that liver tumor-reactive CD8+ T failed to control liver tumors but was effective against subcutaneous tumors. Similarly, analysis of single-cell RNA sequencing data from patients showed a higher frequency of exhausted tumor-reactive CD8+ T cells in liver metastasis compared to paired primary colon cancer. High-dimensional, multi-omic analysis combining proteomic CODEX and scRNA-seq data revealed enriched interaction of SPP1+ macrophages and CD8+ tumor-reactive T cells in profibrotic, alpha-SMA rich regions in the liver. Liver tumors grew less in Spp1-/- mice and the tumor-specific CD8+ T cells were less exhausted. Differential pseudotime trajectory inference analysis revealed extrahepatic signaling promoting an intermediate cell (IC) population in the liver, characterized by co-expression of VISG4, CSF1R, CD163, TGF-{beta}R, IL-6R, SPP1. scRNA-seq of a third data set of premetastatic adenocarcinoma showed that enrichment of this population may predict liver metastasis. Our data suggests a mechanism by which extrahepatic tumors facilitate the formation of liver metastasis by promoting an IC population inhibiting tumor-reactive CD8+ T cell function.

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Trehan, R. S., Zhu, X. B., Huang, P., Wang, X., Soliman, M., Strepay, D., Nur, A., Kedei, N., Arhin, M., Ghabra, S., Rodriguez Matos, F., Benmebarek, M.-R., Ma, C., Korangy, F., Greten, T. F.. 2024-09-24. A Paradoxical Tumor Antigen Specific Response in the Liver. https://doi.org/10.1101/2024.09.19.614002

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