Improved tumor elimination by anti-tumor T cells that are resistant to adenosine-mediated immunosuppression in tumor microenvironment (95.1)

Abstract

Abstract Tumors protect themselves from the anti-tumor immune response. One of the self-protective mechanisms is extracellular adenosine in tumor microenvironment, which inactivates anti-tumor T cells via A2A adenosine receptor (A2AR). Anti-tumor T cells that are resistant to adenosine-mediated immunosuppression should be of significant benefit to improve adoptive tumor immunotherapy. Our previous study demonstrated that addition of an adenosine receptor agonist NECA in CTL culture made the CTL resistant to adenosine-mediated immunosuppression. In this study, we evaluated the efficacy of NECA-treated anti-tumor T cells in MCA205 lung metastasis model. Culture-activated tumor-draining lymph node cells (TDLN) were used as anti-MCA205 effector cells. It was confirmed that NECA treatment of TDLN are less sensitive to A2AR signaling. We transferred either TDLN or NECA-treated effector cells (NECA-TDLN) into tumor-bearing mice 10 days after tumor inoculation. NECA pretreatment improved tumor rejection as indicated by the decreased number of tumor nodules from 118 ± 51 (TDLN) to 21 ± 33 (NECA-TDLN). T cell proliferation in vivo was analyzed after the adoptive transfer of CFSE-labeled effector cells. NECA-TDLN proliferated better than control TDLN in the lung (tumor site) suggesting that adenosine-resistant NECA-TDLN could activate well in tumor microenvironment. Induction of adenosine-resistance by NECA pretreatment might be a novel approach to overcome immunosuppression in tumors.