Tumor‐specific CD4+ T cells maintain effector and memory tumor‐specific CD8+ T cells

• Published in: European journal of immunology Vol. 44; no. 1; pp. 69 - 79
• Main Authors: Church, Sarah E., Jensen, Shawn M., Antony, Paul A., Restifo, Nicholas P., Fox, Bernard A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2014; BlackWell Publishing Ltd
• Subjects: Animals; Antigens, Neoplasm - immunology; Cancer immunotherapy; Cancer Vaccines - immunology; CD4+ T‐cell help; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Communication; Cellular Immune Response; Cellular Microenvironment; Cytotoxicity, Immunologic; Drug therapy; Female; Immunologic Memory; Immunotherapy; Immunotherapy, Adoptive - methods; Immunotherapy, Adoptive - trends; Lymphocytes; Male; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metastatic melanoma; Mice; Mice, Knockout; Mice, Transgenic; Oxidoreductases - genetics; Oxidoreductases - metabolism; PD‐1; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; T cell; Metastatic melanoma; CD4+ T-cell help; Cancer immunotherapy; PD-1; T cell
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201343718

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.