Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Abstract

Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39 C gdTreg in human colorectal cancer (CRC). CD39 C gdTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4 C or CD8 C Tregs via the adenosine-mediated pathway but independent of TGF-b or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-b1 induces CD39 C gdT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39 C gdTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39 C gdTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.

The expanding family of noncanonical regulatory cell subsets

“…Atsushi et al. proposed that CD39 was a candidate surface marker for regulatory γδ T cells in IL‐10 knockout mice, which has been confirmed by further in‐depth studies . Peters et al.…”

γδ cells and tumor microenvironment: A helpful or a dangerous liason?

“…37 In vivo tumor-infiltrating reg cells could be induced by IP-10 secreted by breast cancer cells 38 indicating that these cells may play an important role to induce the immunosuppressive microenvironment in human CRC. 40 Finally, as demonstrated by several studies on different cancer, T cells showed a dual role in tumor immunity and it seems clearly associated with their complex surrounding microenvironment, which influences T cell polarization.…”

“…have identified a novel CD39 + γδreg cell population in CRC that exerts an immunosuppressive activity via the adenosine‐mediated pathway; these cells also secrete cytokines including IL‐17A and GM‐CSF that are able to chemoattract MDSCs, thus establishing an immunosuppressive network. Concerning their protumoral functions, the authors showed that CD39 + γδreg infiltration was positively correlated with the tumour node metastasis (TNM) stage and other unfavorable clinicopathological features, indicating that these cells may play an important role to induce the immunosuppressive microenvironment in human CRC …”

γδ T Cells: Unexpected Regulators of Cancer Development and Progression

“…Traxlmayr et al found during clinical trial studies that DC production of IL-12 and pyrophosphate activation can in fact induce regulatory γδ T cell responses capable of hampering the proliferative capabilities of tumor-specific CD4 and CD8 T cells (47). A recent study demonstrated that tumor-infiltrating CD39 + γδ T cells have potent immunosuppressive activity via secretion of adenosine in human colorectal cancer (48). More investigation is needed to better characterize which γδ T cell populations are capable of becoming regulatory and how these suppressive populations operate in situ .…”