title: Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients.
abstract: CTLA-4 is a surface receptor on activated T cells that delivers an inhibitory signal, serving as an immune checkpoint. Treatment with anti-CTLA-4 Abs can induce clinical responses to different malignancies, but the nature of the induced Ag-specific recognition is largely unknown. Using microarrays spotted with >8000 human proteins, we assessed the diversity of Ab responses modulated by treatment with CTLA-4 blockade and GM-CSF. We find that advanced prostate cancer patients who clinically respond to treatment also develop enhanced Ab responses to a higher number of Ags than nonresponders. These induced Ab responses targeted Ags to which preexisting Abs are more likely to be present in the clinical responders compared with nonresponders. The majority of Ab responses are patient-specific, but immune responses against Ags shared among clinical responders are also detected. One of these shared Ags is PAK6, which is expressed in prostate cancer and to which CD4(+) T cell responses were also induced. Moreover, immunization with PAK6 can be both immunogenic and protective in mouse tumor models. These results demonstrate that immune checkpoint blockade modulates Ag-specific responses to both individualized and shared Ags, some of which can mediate anti-tumor responses.
authors.affiliation: Division of Hematology/Oncology, Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Serena S
authors.initials: SS
authors.lastname: Kwek
authors.forename: Vinh
authors.initials: V
authors.lastname: Dao
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.forename: Yafei
authors.initials: Y
authors.lastname: Hou
authors.forename: David
authors.initials: D
authors.lastname: Alajajian
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Simko
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000916:Antibody Diversity; D000951:Antigens, Neoplasm / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis* / Q000276:immunology*; D005240:Feasibility Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation / Q000276:immunology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D001323:Autoantibodies; D001324:Autoantigens; D060908:CTLA-4 Antigen; D018984:Epitopes, T-Lymphocyte; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor