Tumor‐specific CD4+ T cells maintain effector and memory tumor‐specific CD8+ T cells. Issue 1 (21st November 2013)

• Record Type: Journal Article
• Authors: Church, Sarah E.; Jensen, Shawn M.; Antony, Paul A.; Restifo, Nicholas P.; Fox, Bernard A.
• Is Part Of: European journal of immunology. Volume 44:Issue 1(2014:Jan.)
• Page Start: 69
• Page End: 79
• Publication Date: 2013-11-21
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201343718
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor‐specific CD4<sup>+</sup> T cells enhance CD8<sup>+</sup> T‐cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase‐related protein 1‐specific CD4<sup>+</sup> transgenic T cells‐CD4<sup>+</sup> T cells and pmel‐CD8<sup>+</sup> T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (<italic>p</italic> ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8<sup>+</sup> T cells with tumor‐specific cytokine expression. When combined with CD4<sup>+</sup> T cells, transfer of total (naïve and effector) or effector CD8<sup>+</sup> T cells were highly effective, suggesting CD4<sup>+</sup> T cells can help mediate therapeutic effects by maintaining function of activated CD8<sup>+</sup> T cells. In addition, CD4<sup>+</sup> T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (<italic>p</italic> < 0.001) reduced therapeutic efficacy. The CD8<sup>+</sup> T cells recovered from mice treated with both CD8<sup>+</sup> and CD4<sup>+</sup> T cells had decreased expression of PD‐1 and PD‐1‐blockade enhanced the therapeutic efficacy of pmel‐CD8 alone, suggesting that CD4<sup>+</sup> T cells help reduce CD8<sup>+</sup> T‐cell exhaustion. These data support combining immunotherapies that elicit both tumor‐specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells for treatment of patients with cancer.</p> </abstract>