A Paradoxical Tumor Antigen Specific Response in the Liver
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Le résumé fourni par la source
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-βR, 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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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A Paradoxical Tumor Antigen Specific Response in the Liver
- Date Crossref
- 24/09/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Institutes of Health NCI CCR Liver Cancer Program pays non établi dans la noticeOrganisme public
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National Cancer Institute Center for Cancer Research pays non établi dans la noticeOrganisme public
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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National Institute on Deafness and Other Communication Disorders Auditory Development and Restoration Program pays non établi dans la noticeOrganisme public
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Office of the Director pays non établi dans la noticeInstitution
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National Institute of Neurological Disorders and Stroke pays non établi dans la noticeStructure de recherche
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Marymount University pays non établi dans la noticeUniversité ou école supérieure
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National Institute of Neurological Diseases and Stroke Neurosurgery Unit for Pituitary and Inheritable Diseases pays non établi dans la noticeStructure de recherche
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Senior author pays non établi dans la noticeInstitution
NCI CCR Liver Cancer Program — National Institutes of Health, Center for Cancer Research — National Cancer Institute et Center for Cancer Research, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.