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

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. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA Weinheim.