Genetic alteration of an endogenous cell constitutes the initial trigger in tumor development. Prevention and chemotherapy have dramatically ameliorated the prognosis of many cancers. However, it has become clear that immunotherapeutic strategies can definitely contribute to the cure and possibly eradication of cancer. Within this therapeutic rationale, therapies with tumor specific chimeric antigen receptor (CAR) T cells or immune checkpoint inhibitors have provided extraordinary results also in a fraction of incurable patients.
Whereas therapies with CAR T cells have produced spectacular results in the fight against blood malignancies, no such success could be reproduced in the therapy of solid tumours. The reason for this failure is also due to peculiar features of the tumor microenvironment (TME), which suppress the cytotoxic response of tumor infiltrating lymphocytes (TILs). A study by the Grassi lab at IRB has shown that adenosine triphosphate (ATP), a cellular metabolite that is released at high concentrations in the TME because of the aberrant regulation of the neoplastic tissue, induces cellular senescence in TILs, thereby limiting their accumulation in the TME. Extracellular ATP in the TME causes the activation of an ATP-gated ion channel named P2X7 in TILs, that provokes an increase in reactive oxygen species (ROS) and genetic damage, causing TILs to arrest expanding and undergo stress-induced cellular senescence. Switching off P2X7 in TILs caused their rejuvenation, enhanced accumulation in TME and inhibition of tumor growth. The study hypothesizes that P2X7 inhibition might improve the tumoricidal potential of CAR T cells or TILs expanded in vitro in immunotherapeutic approaches for patients bearing solid tumors.
The study has been published in the renowned Cancer Research and was conducted in collaboration with researchers from the Italian Universities of Milan, Modena-Reggio Emilia and Ferrara, and the National Institute of Molecular Genetics of Milan. The work was funded by the Swiss Cancer Research Foundation, Swiss National Science Foundation, Fondazione Gelu, Fondazione per la Ricerca sulla Trasfusione e sui Trapianti, AIRC Foundation for Cancer Research, Italian National Research Council and Italian Ministry of Health.
P2X7 receptor activity limits accumulation of T cells within tumors
A. Romagnani, E. Rottoli, E. M. C. Mazza, T. Rezzonico-Jost, B. De Ponte Conti, M. Proietti, M. Perotti, E. Civanelli, L. Perruzza, A. L. Catapano, A. Baragetti, E. Tenedini, E. Tagliafico, S. Falzoni, F. Di Virgilio, G. D. Norata, S. Bicciato, F. Grassi
in Cancer Res (2020)