Frontiers in Immunology (Jan 2024)

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

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

DOI
https://doi.org/10.3389/fimmu.2023.1295208
Journal volume & issue
Vol. 14

Abstract

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IntroductionEpithelial 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.MethodsWe 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.ResultsAnalysis 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.DiscussionThese 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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