Anales RANF

S10-02 P2X7 RECEPTOR IS A KEY REGULATOR OF ATP CONTENT AND IMMUNE INFILTRATION IN THE TUMOR MICROENVIRONMENT E. De Marchi 1 , E. Oriol i1 , A. Pegoraro 1 , S. Sangaletti 2 , P. Portararo 2 , A. Curti 3 , M. P. Colombo 2 , F. Di Virgilio 1 , E. Adinolfi 1 1 . University of Ferrara, Ferrara, Italy, 2 . Istituto Nazionale dei Tumori, Milano; Italy, 3 . Institute of Hematology L. and A. Seràgnoli, Bologna, Italy. P2X7 is an ATP gated ion channel that attracted increasing attention as potential oncological target. P2X7 blockade reduces cancer growth in various preclinical models. However, and rather surprisingly, tumor growth and dissemination are increased in P2X7 null mice. This apparent paradox is due to reduced immune cell infiltration in tumors growing in the P2X7 null host compared to their wild type counterpart, suggesting that lack of P2X7 hampers tumor-immune cell infiltration. Here we investigated the mechanism by which P2X7 genetic deletion or pharmacological blockade modulate tumor immune contexture. In the P2X7 null host, an immunosuppressive infiltrate, characterized by fewer CD8 + and an increased number of Tregs, predominates. Furthermore, Tregs express high levels of fitness markers OX40, PD-1 and CD73. On the contrary, P2X7 pharmacological blockade in the P2X7 WT host, supports a tumor-aggressive infiltrate characterized by a high number of CD4 + effector T lymphocytes, reduced expression of OX40 on Tregs and of CD39 and CD73 on Teffs and dendritic cells. Genetic deletion versus pharmacological blockade of the P2X7 receptor also had a differential effect on the ATP content of the tumor microenvironment, as while in the former case we observed a large reduction in ATP concentration, no changes were observed in the latter. Our findings show that the P2X7 receptor is a crucial determinant of tumor-host interaction since its expression and function affect both immune cell infiltration and ATP content in the tumor milieu. P2X7 pharmacological blockade does not replicate the immunosuppressive effects due to genetic ablation, rather it enhances tumor infiltration by CD4 + T effector cells and diminishes CD39 and CD73 expression, thus reducing immunosuppression. Our observations support the hypothesis that administration of P2X7 antagonists may be a viable therapy for cancer, combining the direct inhibitory effect on tumor growth with the promotion of a tumor-aggressive immune infiltrate.