title: PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors.
abstract: Tn is a carbohydrate antigen uniquely exposed on tumor mucins and, thus, an ideal target for immunotherapy. However, it has been difficult to elicit protective antibody responses against Tn antigen and other tumor-associated carbohydrate antigens. Our study demonstrates this can be attributed to PD-1 immuno-inhibition. Our data show a major role for PD-1 in suppressing mucin- and Tn-specific B-cell activation, expansion, and antibody production important for protection against Tn-bearing tumor cells. These Tn/mucin-specific B cells belong to the innate-like B-1b cell subset typically responsible for T cell-independent antibody responses. Interestingly, PD-1-mediated regulation is B cell-intrinsic and CD4+cells play a key role in supporting Tn/mucin-specific B-cell antibody production in the context of PD-1 deficiency. Mucin-reactive antibodies produced in the absence of PD-1 inhibition largely belong to the IgM subclass and elicit potent antitumor effects via a complement-dependent mechanism. The identification of this role for PD-1 in regulating B cell-dependent antitumor immunity to Tn antigen highlights an opportunity to develop new therapeutic strategies targeting tumor-associated carbohydrate antigens. Cancer Immunol Res; 4(12); 1027-37. ©2016 AACR.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Haro
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Littrell
authors.affiliation: Department of Chemistry, Michigan State University, East Lansing, Michigan.
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Chemistry, Michigan State University, East Lansing, Michigan.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina. kmhaas@wakehealth.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Haas
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009077:Mucins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009077:Mucins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C040286:Tn antigen