Nelson and Knochelmann et al. report that CD26high CD4+ T cells represent a distinct population of CD4+ helper T cells with potent antitumor properties. CD26high CD4+ T cells differ from TH1, TH2, and TH17 cells based on surface markers, increased cytokine production (IL-17, IFNγ, IL-22, and IL-2), epigenetic landscape, and gene expression patterns. CD26high CD4+ T cells expressing first generation mesothelin-specific CAR increased CD4+ and CD8+ CAR T cell persistence in vivo, eradicated large established mesothelioma tumors, and increased survival independent of IL-17 and CD26 expression and of CD8+ CAR T cells.
Contributed by Shishir Pant
ABSTRACT: How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies.
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. (2) Department of Dermatology and Dermatologic Surgery, Medical University
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. (2) Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, SC, USA. (3) Department of Surgery, Medical University of South Carolina, Charleston, SC, USA. (4) Department of Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA. (5) Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA. (6) Epinomics, Menlo Park, CA, USA. (7) Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA. (8) Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
