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Publications

Journal Article Epublish

PubMed: 42326466 DOI: 10.1093/immadv/ltag010

NLRC5 expression within tumor cells is critical to activate adaptive and innate antitumor immune responses.

Immunother Adv 6(1):ltag010

Authors: Akhil Shukla, Mohammad Moradzad, Akouavi Julite Irmine Quenum, Jean-François Lucier, Anny Armas Cayarga, Dominique Lévesque, François-Michel Boisvert, Thomas A Kufer, Sheela Ramanathan, Subburaj Ilangumaran

Affiliations

  • Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
  • Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
  • Department of Biology, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
  • Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
  • Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.

Abstract

INTRODUCTION

Tumors downregulate NLRC5 expression to reduce MHC-I and evade CD8 + T cell-mediated killing. Introducing full-length NLRC5 (N5FL) or NLRC5-CIITA chimeric protein (N5CA) can restore tumor immunogenicity. Here, we elucidated the underlying mechanisms and also evaluated the requirement of NLRC5 expression in antigen-presenting cells (APCs) of the host for tumor control.

MATERIALS AND METHODS

and mice were implanted with B16-F10 melanoma expressing N5FL or NC5A. Tumor growth, activation of lymphoid cells, their infiltration into tumors and the requirement for tumor control were assessed. The proteomes of B16-F10 cells expressing N5FL or N5CA were analyzed.

RESULTS

NLRC5-expressing tumors were efficiently controlled in both and mice, characterized by infiltration of CD8 + and CD4 + cells, natural killer (NK) cells, NK T (NKT) cells and invariant NKT (iNKT) cells, increased tumor vascularization and upregulation of Ccl4 and Cxcl9 genes. Both CD8 + and NK1.1 + cells contribute to NLRC5-dependent tumor control. NLRC5 expression in the Tumor Cancer Genome Atlas-skin cutaneous melanoma correlated with NK cell markers and nonclassical MHC-Ib expression. Proteomes of NLRC5-expressing tumor cells showed downmodulation of dominant tumor antigens, but displayed significant changes in the lysosome and the proteasome pathways, upregulated the protein processing in endoplasmic reticulum pathway, and downregulated the autophagy pathway, all of which could impact processing and presentation of subdominant tumor antigens.

CONCLUSION

NLRC5 expression in APCs is dispensable for NLRC5-dependent antitumor immunity. NLRC5-dependent tumor control requires both CD8 + and NK1.1 + cells. Tumor-intrinsic NLRC5 promotes vasculature that is permissive to infiltration by antitumor immune cells. In addition to upregulating MHC-I, NLRC5 may enhance alternative antigen-processing pathways and attenuate autophagic degradation of MHC-I, thereby augmenting tumor immunogenicity.

MeSH

Cells, Killer Cells, Natural, Melanoma, Neoplasms, Immunity, Tumor Microenvironment, Immune Evasion