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

Galaxia M Rodriguez; Edward Yakubovich; Humaira Murshed; Vincent Maranda; Kristianne J C Galpin; Alison Cudmore; Andrew M R Hanna; Elizabeth Macdonald; Shashankan Ramesh; Kenneth Garson; Barbara C Vanderhyden

doi:10.3389/fimmu.2023.1295208

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

Front Immunol. 2024 Jan 3:14:1295208. doi: 10.3389/fimmu.2023.1295208. eCollection 2023.

Authors

Galaxia M Rodriguez^{1

2}, Edward Yakubovich^{1

2}, Humaira Murshed¹, Vincent Maranda¹, Kristianne J C Galpin^{1

2}, Alison Cudmore^{1

2}, Andrew M R Hanna¹, Elizabeth Macdonald^{1

2}, Shashankan Ramesh^{1

2}, Kenneth Garson^{1

2}, Barbara C Vanderhyden^{1

2}

Affiliations

¹ Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
² Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Abstract

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.

Keywords: MHC I; NLRC5; infected cell vaccine; ovarian cancer; tumor immunogenicity; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm
Caspase Activation and Recruitment Domain
Female
Histocompatibility Antigens Class I
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Mice
NLR Proteins
Ovarian Neoplasms* / genetics
Tumor Microenvironment
Vaccines*

Substances

NLR Proteins
Intracellular Signaling Peptides and Proteins
Histocompatibility Antigens Class I
Antigens, Neoplasm
Vaccines
NLRC5 protein, human
NLRC5 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Canadian Institutes of Health Research (CBT-390261 and CBT-486795; BCV). Additional support was provided by a fellowship from the Fonds de Recherche du Québec (GR), a CIHR Canada Graduate Scholarship (KJCG), and a QEII scholarship (AC).