title: NLRC5 elicits antitumor immunity by enhancing processing and presentation of tumor antigens to CD8(+) T lymphocytes.
abstract: Cancers can escape immunesurveillance by diminishing the expression of MHC class-I molecules (MHC-I) and components of the antigen-processing machinery (APM). Developing new approaches to reverse these defects could boost the efforts to restore antitumor immunity. Recent studies have shown that the expression of MHC-I and antigen-processing molecules is transcriptionally regulated by NOD-like receptor CARD domain containing 5 (NLRC5). To investigate whether NLRC5 could be used to improve tumor immunogenicity, we established stable lines of B16-F10 melanoma cells expressing NLRC5 (B16-5), the T cell co-stimulatory molecule CD80 (B16-CD80) or both (B16-5/80). Cells harboring NLRC5 constitutively expressed MHC-I and LMP2, LMP7 and TAP1 genes of the APM. The B16-5 cells efficiently presented the melanoma antigenic peptide gp10025-33 to Pmel-1 TCR transgenic CD8(+) T cells and induced their proliferation. In the presence of CD80, B16-5 cells stimulated Pmel-1 cells even without the addition of gp100 peptide, indicating that NLRC5 facilitated the processing and presentation of endogenous tumor antigen. Upon subcutaneous implantation, B16-5 cells showed markedly reduced tumor growth in C57BL/6 hosts but not in immunodeficient hosts, indicating that the NLRC5-expressing tumor cells elicited antitumor immunity. Following intravenous injection, B16-5 and B16-5/80 cells formed fewer lung tumor foci compared to control cells. In mice depleted of CD8(+) T cells, B16-5 cells formed large subcutaneous and lung tumors. Finally, immunization with irradiated B16-5 cells conferred protection against challenge by parental B16 cells. Collectively, our findings indicate that NLRC5 could be exploited to restore tumor immunogenicity and to stimulate protective antitumor immunity.
authors.affiliation: Immunology division, Department of Pediatrics.
authors.forename: Galaxia M
authors.initials: GM
authors.lastname: Rodriguez
authors.affiliation: Immunology division, Department of Pediatrics.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Bobbala
authors.affiliation: Immunology division, Department of Pediatrics.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serrano
authors.affiliation: Immunology division, Department of Pediatrics.
authors.forename: Marian
authors.initials: M
authors.lastname: Mayhue
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , Sherbrooke, Quebec, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Champagne
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; CRCHUS, Sherbrooke, Québec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Saucier
authors.affiliation: Department of Biology, Faculty of Sciences, Université de Sherbrooke , Sherbrooke, Quebec, Canada.
authors.forename: Viktor
authors.initials: V
authors.lastname: Steimle
authors.affiliation: Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim , Stuttgart, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
authors.affiliation: CRCHUS, Sherbrooke, Québec, Canada; Department of Microbiology and Infectious diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Menendez
authors.affiliation: Immunology division, Department of Pediatrics; CRCHUS, Sherbrooke, Québec, Canada.
authors.forename: Sheela
authors.initials: S
authors.lastname: Ramanathan
authors.affiliation: Immunology division, Department of Pediatrics; CRCHUS, Sherbrooke, Québec, Canada.
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
keywords: B16-F10; CD8+ T cells; CD80; MHC class-I; Melanoma; NLRC5; Pmel-1