title: Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses.
abstract: Tumor antigen-specific CD4(+) T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4(+) T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4(+) helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4(+) T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8(+) T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8(+) T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients.
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA.|Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
authors.affiliation: TAKARA BIO INC, Otsu, Shiga, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.affiliation: TAKARA BIO INC, Otsu, Shiga, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Departments of Immunology, Molecular Pharmacology and Experimental Therapeutics, and Research, Mayo Clinic-Arizona, Scottsdale, AZ, USA.
authors.forename: Protul
authors.initials: P
authors.lastname: Shrikant
authors.affiliation: Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma