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.