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