CD26high T cells have a natural capacity to migrate and persist in multiple tumor models
Stefanie R. Bailey1,2,3*, Michelle H. Nelson1,2,3, Jacob S. Bowers1,2,3, Megan M. Wyatt1,2,3, Lillian R. Neal1,2,3, Kinga Majchrzak1,2,3, Chrystal M. Paulos1,2,3*
1Department of Microbiology & Immunology, 2Department of Surgery, 3Department of Dermatology
Adoptive T cell transfer (ACT) has been an impressive therapy for treating cancer patients, but can be inconsequential if the transferred cells are unable to engraft and persist. Although adoptive transfer of Th17 cells has exhibited enhanced anti-tumor activity and persistence in mouse models, their translation to the clinic is barred by a lack of FDA-approved cytokines needed to expand them. Consequently, we sought to determine if we could enrich and expand durable, human IL-17-producing T cells without the use of polarizing cytokines. Our lab has found that isolating human CD4+ T cells that express high levels of CD26—termed CD26high T cells—not only exhibit a Th17-like phenotype (CCR6, CD161), but also display the Th1 marker CXCR3, are polyfunctional (IL-17, IFNγ, IL-2, TNFα, IL-22) and have heightened cytotoxicity (CD107A, Granzyme B) in vitro—all in the absence of polarizing cytokines. Of clinical significance, CD26high T cells displayed striking antitumor activity in NSG mice bearing large, established mesothelioma and pancreatic tumors to a greater extent than bulk CD4+ and CD26negative T cells. CD26high T cells exhibited an enhanced capacity to migrate to the tumor due to their natural expression of the chemokine receptors CCR2 and CCR5. Importantly, CD26high T cells also exhibited increased persistence in the tumor despite their more differentiated phenotype (CD45RA-CCR7-CD45RO+) in vitro.CD26high T cells were found to express elevated levels of β-catenin and BCL-2, as well as decreased Caspase 3 cleavage, which could drive their long-term persistence. Collectively, these findings reveal the highly cytotoxic, migratory and anti-apoptotic nature of CD26high T cells that make them ideal for improving ACT in the clinic.
Funding: F31 CA192787 (NCI), RO1 CA175061 (NCI), RO1 CA208514 (NCI)