CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function

// Filip Ahlmanner 1 , Patrik Sundström 1 , Paulina Akeus 1 , Jenny Eklöf 1 , Lars Börjesson 2 , Bengt Gustavsson 2 , Elinor Bexe Lindskog 2 , Sukanya Raghavan 1 and Marianne Quiding-Järbrink 1 1 Department of Microbiology and Immunology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden 2 Department of Surgery, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden Correspondence to: Filip Ahlmanner, email: filip.ahlmanner@gu.se Keywords: CD39; regulatory T cells; colon cancer; adenosine; immune checkpoint molecules Received: March 12, 2018 Accepted: November 26, 2018 Published: December 11, 2018 ABSTRACT Increasing knowledge of the function and regulation of tumor-infiltrating lymphocytes has led to new insights in cancer immunotherapy. Regulatory T cells (Treg) accumulate in colon tumors, and we recently showed that CD39 + Treg from cancer patients inhibit transendothelial migration of conventional T cells. CD39 mediates the hydrolysis of ATP to immunosuppressive adenosine and adds to the immunosuppressive effects of Treg. Here, we further investigated the regulatory features of intratumoral CD39 + Treg in colon cancer. Using flow cytometry analyses of cells from 46 colon cancer patients, we confirm the accumulation of CD39 + Treg in the tumor tissue compared to unaffected colon tissue, and also show that tumor-infiltrating Treg express more CD39 and Foxp3 on a per cell basis. Furthermore, CD39 + Treg in tumors express markers indicating increased turnover and suppressive ability. In particular, tumor-infiltrating CD39 + Treg have high expression of surface molecules related to immunosuppression, such as ICOS, PD-L1 and CTLA-4. Functional suppression assays also indicate potent suppressive capacity of CD39 + Treg on proliferation and IFN-γ secretion by conventional T cells. In conclusion, our results identify tumor-infiltrating CD39 + Treg as a numerous and potentially important immunosuppressive subset, and suggest that immunotherapy aimed at reducing the activity of CD39 + Treg may be particularly useful in the setting of colon cancer.