Journal Article

Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

Junko Matsuzaki, Junichi Mineno, Immanuel F. Luescher, Takemasa Tsuji, Protul Shrikant, Kunle Odunsi, Lloyd J. Old, Sacha Gnjatic, Sachiko Okamoto, Hiroshi Shiku

2015

Overview

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.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/107 / 13/109 / 13/21 / 13/31 / 14/34 / 631/250/1619/554 / 631/250/580 / Animals / Animals; Antigens, Neoplasm/immunology; Antigens, Neoplasm/metabolism; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/metabolism; CD8-Positive T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/metabolism; Cell Line, Tumor; Cell Proliferation/drug effects; Cell Survival/drug effects; Cell Survival/immunology; Cells, Cultured; Coculture Techniques; Cytotoxicity, Immunologic/immunology; Female; Humans; Interferon-gamma/immunology; Interferon-gamma/metabolism; Jurkat Cells; Membrane Proteins/immunology; Membrane Proteins/metabolism; Mice, SCID; Ovarian Neoplasms/immunology; Ovarian Neoplasms/pathology; T-Lymphocytes, Helper-Inducer/immunology; T-Lymphocytes, Helper-Inducer/metabolism; Transplantation, Heterologous; Tumor Burden/immunology; Tumor Necrosis Factor-alpha/immunology; Tumor Necrosis Factor-alpha/metabolism / Antigen-presenting cells / Antigens / Antigens, Neoplasm / Antigens, Neoplasm - immunology / Antigens, Neoplasm - metabolism / Cancer / CD4 antigen / CD4-Positive T-Lymphocytes / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Cell Proliferation / Cell Proliferation - drug effects / Cell Survival / Cell Survival - drug effects / Cell Survival - immunology / Cells, Cultured / Coculture Techniques / Cytotoxicity, Immunologic / Cytotoxicity, Immunologic - immunology / Female / Humanities and Social Sciences / Humans / Immune response / Immunology / Interferon-gamma / Interferon-gamma - immunology / Interferon-gamma - metabolism / Interferon-gamma - pharmacology / Jurkat Cells / Lymphocytes / Lymphocytes T / Membrane Proteins / Membrane Proteins - immunology / Membrane Proteins - metabolism / Mice, SCID / multidisciplinary / Ovarian Neoplasms / Ovarian Neoplasms - immunology / Ovarian Neoplasms - pathology / Science / T cell receptors / T-Lymphocytes, Helper-Inducer / T-Lymphocytes, Helper-Inducer - immunology / T-Lymphocytes, Helper-Inducer - metabolism / Transplantation, Heterologous / Tumor Burden / Tumor Burden - immunology / Tumor Necrosis Factor-alpha / Tumor Necrosis Factor-alpha - immunology / Tumor Necrosis Factor-alpha - metabolism / Tumor Necrosis Factor-alpha - pharmacology / Tumors / Xenografts