CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells.

Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy. We and others have previously reported that high-avidity CD8(+) T cells are more susceptible to tolerance induction in the tumor microenvironment. In the present study, we used a novel model where T cells derived from two independent TCR transgenic mouse lines recognize the same melanoma antigenic epitope but differ in their avidity. We tested whether providing CD4(+) T cell help would improve T cell responsiveness as a function of effector T cell avidity. Interestingly, delivery of CD4(+) T cell help during in vitro priming of CD8(+) T cells improved cytokine secretion and lytic capacity of high-avidity T cells, but not low-avidity T cells. Consistent with this observation, copriming with CD4(+) T cells improved antitumor immunity mediated by higher avidity, melanoma-specific CD8(+) T cells, but not T cells with similar specificity but lower avidity. Enhanced tumor immunity was associated with improved CD8(+) T cell expansion and reduced tolerization, and it was dependent on presentation of both CD4(+) and CD8(+) T cell epitopes by the same dendritic cell population. Our findings demonstrate that CD4(+) T cell help preferentially augments high-avidity CD8(+) T cells and provide important insight for understanding the requirements to elicit and maintain durable tumor immunity.