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

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...

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Published in:Frontiers in immunology Vol. 14; p. 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: Journal Article
Language:English
Published: Switzerland Frontiers Media SA 03.01.2024
Frontiers Media S.A
Subjects:
Animals
Antigen (tumor-associated)
Antigen presentation
Antigens
Antigens, Neoplasm
Ascites
Cancer therapies
Caspase Activation and Recruitment Domain
CD4 antigen
CD8 antigen
Cell activation
Cell culture
Cell cycle
Cell recognition
Correlation analysis
Female
Gene expression
Histocompatibility Antigens Class I
Humans
Immunology
Immunotherapy
infected cell vaccine
Intracellular Signaling Peptides and Proteins - metabolism
Leukocyte migration
Lymphocytes
Lymphocytes T
Major histocompatibility complex
Malignancy
Medical prognosis
Metadata
MHC I
Mice
NLR Proteins
NLRC5
Ovarian cancer
Ovarian Neoplasms - genetics
Patients
PD-L1 protein
Peripheral blood
Survival analysis
tumor immunogenicity
Tumor Microenvironment
Tumors
Vaccines
γ-Interferon
NLRC5
infected cell vaccine
tumor immunogenicity
tumor microenvironment
ovarian cancer
MHC I
ISSN:1664-3224, 1664-3224
Online Access:Get full text
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Summary: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.
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Edited by: Alejandro López-Soto, University of Oviedo, Spain
Zuzanna Urban-Wójciuk, University of Gdansk, Poland
Reviewed by: Prathyusha Konda, Dana–Farber Cancer Institute, United States
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2023.1295208