title: Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors.
abstract: CD40 and CD40 ligand (CD40L) are costimulatory molecules that play a pivotal role in the proinflammatory immune response. Primarily expressed by activated CD4+ T cells, CD40L binds to CD40 on antigen presenting cells (APCs), thereby inducing APC activation. APCs, in turn, prime cytotoxic T lymphocytes (CTLs). Here, two tumor-associated antigen (TAA) animal models, p53-based and GP100-based, were utilized to examine the ability of CD40-CD40L to improve antigen-specific CTL-mediated antitumor immune responses. Although p53 and GP100 are self-antigens that generate low affinity antigen-specific CD8+ T cells, studies have shown that their functional avidity can be improved with CD40L-expressing APCs. Therefore, in the current study, we immunized mice with a DNA construct encoding a TAA in conjunction with another construct encoding CD40L via intramuscular injection followed by electroporation. We observed a significant increase in the antigen-specific CTL-mediated immune responses as well as the potent antitumor effects in both models. Antibody depletion experiments demonstrated that CD8+ T cells play a crucial role in eliciting antitumor effects in vaccinated mice. Furthermore, we showed that in vitro stimulation with irradiated tumor cells expressing both TAA and CD40L improved the functional avidity of antigen-specific CD8+ T cells. Thus, our data show that vaccination with TAA/CD40L DNA can induce potent antitumor effects against TAA-expressing tumors through the generation of better functioning antigen-specific CD8+ T cells. Our study serves as an important foundation for future clinical translation.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of General Surgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Ruey-Shyang
authors.initials: RS
authors.lastname: Soong
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Pharmacy School of Fudan University, Shanghai, China; Department of Pharmacology and Toxicology, Shanghai Institute of Planned Parenthood Research, Shanghai, China; Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Song
authors.affiliation: Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Janson
authors.initials: J
authors.lastname: Trieu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of Internal Medicine, Korea University Medical Center, Seoul, South Korea.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Ya-Chea
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D016159:Tumor Suppressor Protein p53; D058951:gp100 Melanoma Antigen; D023201:CD40 Ligand