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

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.

• Authors: Sarah E Church, Shawn M Jensen, Paul A Antony, Nicholas P Restifo, Bernard A Fox
• Journal: European journal of immunology (Eur J Immunol) Vol. 44 Issue 1 Pg. 69-79 (Jan 2014) ISSN: 1521-4141 [Electronic] Germany
• PMID: 24114780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2013 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA Weinheim.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Membrane Glycoproteins
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Oxidoreductases
• Tyrp1 protein, mouse

Topics

• Animals
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology, transplantation)
• CD8-Positive T-Lymphocytes (immunology, transplantation)
• Cancer Vaccines (immunology)
• Cell Communication
• Cellular Microenvironment
• Cytotoxicity, Immunologic
• Female
• Immunologic Memory
• Immunotherapy, Adoptive (methods, trends)
• Male
• Melanoma, Experimental (immunology, therapy)
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Oxidoreductases (genetics, metabolism)
• Programmed Cell Death 1 Receptor (genetics, metabolism)