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.
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Malandro
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sadna
authors.initials: S
authors.lastname: Budhu
authors.affiliation: Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Kuhn
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Cailian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors.forename: Judith T
authors.initials: JT
authors.lastname: Murphy
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Czrina
authors.initials: C
authors.lastname: Cortez
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rizzuto
authors.affiliation: Programs in Computational Biology & Immunology, Memorial Sloan Kettering, New York, NY 10065, USA.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: merghout@mskcc.org.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: wolchokj@mskcc.org.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019139:Tumor Escape / Q000276:immunology*