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However, activation of antigen-specific CD4<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> T cells (TR-CD4) potently induced IFN-\u03b3-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<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> T cells significantly inhibited tumor growth <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/srep14896","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T09:24:20Z","timestamp":1444296260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses"],"prefix":"10.1038","volume":"5","author":[{"given":"Junko","family":"Matsuzaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takemasa","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immanuel F.","family":"Luescher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Shiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Mineno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd J.","family":"Old","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Protul","family":"Shrikant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Gnjatic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunle","family":"Odunsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,8]]},"reference":[{"key":"BFsrep14896_CR1","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/S0952-7915(98)80228-8","volume":"10","author":"DM Pardoll","year":"1998","unstructured":"Pardoll, D. 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