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

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

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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-γ3-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.

Original languageEnglish (US)
Article number14896
JournalScientific Reports
Volume5
DOIs
StatePublished - Oct 8 2015

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Matsuzaki, J., Tsuji, T., Luescher, I. F., Shiku, H., Mineno, J., Okamoto, S., Old, L. J., Shrikant, P., Gnjatic, S., & Odunsi, K. (2015). Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses. Scientific Reports, 5, [14896]. https://doi.org/10.1038/srep14896