Clonal Abundance of Tumor-Specific CD4+ T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion

• Precursor frequency of melanocyte-specific CD4+ T cells dictates anti-tumor efficacy
• Susceptibility to T cell exhaustion increases at low precursor frequencies
• Despite intraclonal competition, high abundance potentiates effector differentiation
• Improved cytotoxicity and Th1 polarization are due to cooperative IFN-γ sharing

SummaryCurrent approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen-specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrated that the clonal abundance of CD4+ T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor-specific CD4+ T cell population. However, through clonally derived help, this population acquired a polyfunctional effector phenotype and antitumor immunity was enhanced. Conversely, development of effector function was attenuated at low precursor frequencies due to irreversible T cell exhaustion. Our findings assert that the differential effects of T cell clonal abundance on phenotypic outcome should be considered during the design of adoptive T cell therapies, including use of engineered T cells.

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