Bailey et al. found that differential expression of CD26, an enzyme that plays a role in T cell costimulation and binding to extracellular matrix proteins, defines three human CD4+ T cell subsets: regulatory (CD26neg), naive (CD26int), and stem memory (CD26high). When used in adoptive cell transfer, CD26high T cells exhibit persistence and promote regression of multiple tumors due to enhanced cytotoxicity, high polyfunctionality, expansive chemokine receptor repertoire, increased co-inhibitory and co-stimulatory markers, and resistance to apoptosis.

CD8(+) T lymphocytes mediate potent immune responses against tumor, but the role of human CD4(+) T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26(neg) T cells possess a regulatory phenotype, CD26(int) T cells are mainly naive and CD26(high) T cells appear terminally differentiated and exhausted. Paradoxically, CD26(high) T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26(high) cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (beta-catenin and Lef1). These properties license CD26(high) T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4(+) T cell subsets with properties critical for improving cancer immunotherapy.

Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. flemins@musc.edu. Department of Surgery, Medical University of South Carolina, Charleston

Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. flemins@musc.edu. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. flemins@musc.edu. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. flemins@musc.edu. (2) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Aptevo Therapeutics, Seattle, WA, 98121, USA. (3) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, 02-787, Poland. (4) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. (5) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. (6) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. (7) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. (8) Hematology/Oncology Division, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA. Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, 02714, USA. (9) Department of Pathology and Laboratory Medicine, University of Pennsylvania Cancer Center, Philadelphia, PA, 19104, USA. Eli Lilly and Company, New York, NY, 10016, USA. (10) Department of Pathology and Laboratory Medicine, University of Pennsylvania Cancer Center, Philadelphia, PA, 19104, USA. (11) Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA. (12) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA. paulos@musc.edu. Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. paulos@musc.edu. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA. paulos@musc.edu.

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