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

• Published in: Frontiers in immunology 2024-01, Vol.14, p.1295208-1295208
• Main Authors: Rodriguez, Galaxia M, Yakubovich, Edward, Murshed, Humaira, Maranda, Vincent, Galpin, Kristianne J C, Cudmore, Alison, Hanna, Andrew M R, Macdonald, Elizabeth, Ramesh, Shashankan, Garson, Kenneth, Vanderhyden, Barbara C
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm; Caspase Activation and Recruitment Domain; Female; Histocompatibility Antigens Class I; Humans; Immunology; infected cell vaccine; Intracellular Signaling Peptides and Proteins - metabolism; MHC I; Mice; NLR Proteins; NLRC5; ovarian cancer; Ovarian Neoplasms - genetics; tumor immunogenicity; Tumor Microenvironment; Vaccines
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1295208

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. 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. 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. 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.