Tumor‐specific CD4+ T cells maintain effector and memory tumor‐specific CD8+ T cells |
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Authors: | Sarah E. Church Shawn M. Jensen Paul A. Antony Nicholas P. Restifo Bernard A. Fox |
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Affiliation: | 1. Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA;2. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA;3. Department of Microbiology and Immunology, University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA;4. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;5. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA |
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Abstract: | Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor‐specific CD4+ T cells enhance CD8+ T‐cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase‐related protein 1‐specific CD4+ transgenic T cells‐CD4+ T cells and pmel‐CD8+ T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8+ T cells with tumor‐specific cytokine expression. When combined with CD4+ T cells, transfer of total (naïve and effector) or effector CD8+ T cells were highly effective, suggesting CD4+ T cells can help mediate therapeutic effects by maintaining function of activated CD8+ T cells. In addition, CD4+ T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8+ T cells recovered from mice treated with both CD8+ and CD4+ T cells had decreased expression of PD‐1 and PD‐1‐blockade enhanced the therapeutic efficacy of pmel‐CD8 alone, suggesting that CD4+ T cells help reduce CD8+ T‐cell exhaustion. These data support combining immunotherapies that elicit both tumor‐specific CD4+ and CD8+ T cells for treatment of patients with cancer. |
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Keywords: | Cancer immunotherapy CD4+ T‐cell help Metastatic melanoma PD‐1 T cell |
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