Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.

Autor:	Cohen Shvefel S; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Pai JA; Department of Pathology, Stanford University, Stanford, CA, USA., Cao Y; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Pal LR; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Levy R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Yao W; Department of Pathology, Stanford University, Stanford, CA, USA., Cheng K; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.; MSD R&D (China) Co., Ltd., Zemanek M; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Bartok O; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Weller C; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Yin Y; Department of Pathology, Stanford University, Stanford, CA, USA., Du PP; Department of Pathology, Stanford University, Stanford, CA, USA., Yakubovich E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Orr I; Bioinformatics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Ben-Dor S; Bioinformatics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Oren R; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel., Fellus-Alyagor L; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel., Golani O; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Goliand I; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Ranmar D; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Savchenko I; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel., Ketrarou N; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel., Schäffer AA; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Ruppin E; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Satpathy AT; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Samuels Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 29. Date of Electronic Publication: 2023 Nov 29.
DOI:	10.1101/2023.11.29.569032
Abstrakt:	Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data. Competing Interests: Conflict of interest: A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Astellas and Merck Research Laboratories. E.R. is a co-founder of MedAware Ltd and a co-founder (divested) and non-paid scientific consultant of Pangea Biomed. The other authors declare that they have no potential conflicts of interest.
Databáze:	MEDLINE
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