Clonal abundance of tumor-specific CD4(+) T cells potentiates efficacy and alters susceptibility to exhaustion Journal Article
| Authors: | Malandro, N.; Budhu, S.; Kuhn, N. F.; Liu, C.; Murphy, J. T.; Cortez, C.; Zhong, H.; Yang, X.; Rizzuto, G.; Altan-Bonnet, G.; Merghoub, T.; Wolchok, J. D. |
| Article Title: | Clonal abundance of tumor-specific CD4(+) T cells potentiates efficacy and alters susceptibility to exhaustion |
| Abstract: | Current 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. Self-reactive tumor-specific CD4+ T cells are eliminated from the immune repertoire during negative selection. Wolchok and colleagues demonstrate that the clonal abundance of melanocyte-specific CD4+ T cells instructs the development effector function and shapes the potential for T cell exhaustion with profound effects on anti-tumor efficacy. © 2016 Elsevier Inc. |
| Journal Title: | Immunity |
| Volume: | 44 |
| Issue: | 1 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2016-01-19 |
| Start Page: | 179 |
| End Page: | 193 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2015.12.018 |
| PROVIDER: | scopus |
| PUBMED: | 26789923 |
| PMCID: | PMC4996670 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 April 2016 -- Source: Scopus |
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