NLRC5 overexpression in ovarian tumors remodels the tumor microenvironment and increases T-cell reactivity toward autologous tumor-associated antigens.

Autor:	Rodriguez GM; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Yakubovich E; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Murshed H; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada., Maranda V; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada., Galpin KJC; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Cudmore A; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Hanna AMR; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada., Macdonald E; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Ramesh S; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Garson K; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada., Vanderhyden BC; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jan 03; Vol. 14, pp. 1295208. Date of Electronic Publication: 2024 Jan 03 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1295208
Abstrakt:	Introduction: Epithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components. We therefore explored the therapeutic potential of NLRC5 in OC. Methods: We generated OC cells overexpressing NLRC5 to rescue MHC I expression and antigen presentation and then assessed their capability to respond to PD-L1 blockade and an infected cell vaccine. Results: Analysis of microarray datasets revealed a correlation between elevated NLRC5 expression and extended survival in OC patients; however, NLRC5 was scarcely detected in the OC tumor microenvironment. OC cells overexpressing NLRC5 exhibited slower tumor growth and resulted in higher recruitment of leukocytes in the TME with lower CD4/CD8 T-cell ratios and increased activation of T cells. Immune cells from peripheral blood, spleen, and ascites from these mice displayed heightened activation and interferon-gamma production when exposed to autologous tumor-associated antigens. Finally, as a proof of concept, NLRC5 overexpression within an infected cell vaccine platform enhanced responses and prolonged survival in comparison with control groups when challenged with parental tumors. Discussion: These findings provide a compelling rationale for utilizing NLRC5 overexpression in "cold" tumor models to enhance tumor susceptibility to T-cell recognition and elimination by boosting the presentation of endogenous tumor antigens. This approach holds promise for improving antitumoral immune responses in OC. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Rodriguez, Yakubovich, Murshed, Maranda, Galpin, Cudmore, Hanna, Macdonald, Ramesh, Garson and Vanderhyden.)
Databáze:	MEDLINE
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