Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence

Stefanie R Bailey,Carmine Carpenito,Aubrey S Smith,Chrystal M Paulos,Michelle H Nelson,Kinga Majchrzak,Michael J Zilliox,Keisuke Shirai,Jacob S Bowers,Megan M Wyatt,Lillian R Neal,Carl H June

doi:10.1038/s41467-017-01867-9

Abstract

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 CD26neg T cells possess a regulatory phenotype, CD26int T cells are mainly naive and CD26high T cells appear terminally differentiated and exhausted. Paradoxically, CD26high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26high 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 (β-catenin and Lef1). These properties license CD26high 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.

Highlights

CD8+ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4+ T cell subsets in cancer immunotherapy remains ill-defined
A mere 50,000 CD26high T cells were more effective at clearing B16F10 melanoma tumor than 50,000 CD26neg T cells when infused into lymphodepleted mice (Supplementary Fig. 1a, b)
Half of the mice treated with CD26high T cells experienced a curative response (Supplementary Fig. 1c)

Summary

Introduction

CD8+ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4+ T cell subsets in cancer immunotherapy remains ill-defined. Further analysis revealed that CD26high 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 (β-catenin and Lef[1]). These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors. These findings identify CD4+ T cell subsets with properties critical for improving cancer immunotherapy. Given the substantial IL-17 production from CD26high T cells, we postulated that CD26 expression on CD4+ T cells might correlate with a more stem cell-like lymphocyte with enhanced tumor regression

Methods

Results

Conclusion