Simon C. Robson
Beth Israel Deaconess Medical Center, Division of Gastroenterology and Hepatology, Harvard Medical School, Boston, MA 02215, USA
Tumors appear to grow by recruiting a range of protective immune suppressive pathways that prevent the cancer cells being recognized as foreign or dangerous and allow evasion of immune elimination. There are multiple means by which tumors subvert host responses, which can limit inflammatory reactions and induce tolerance towards tumor-antigens. Immunotherapies are newly developing interventions that modify the patient’s immune system to fight cancer, by either directly stimulating rejection-type processes or by blocking suppressive pathways. These innovative approaches include chimeric antigen receptor (CAR) T cell therapy and checkpoint blockade with immunomodulatory antibodies (e.g. anti-CTLA-4, anti-PD-1), which have brought much hope to cancer patients. Standard cancer therapies, including radiotherapy, also seem to require the active involvement of the patient’s immune system for efficacy.
Our focus has been on the regulation of purinergic signaling by the ectonucleotidases CD39, which catalyzes phosphohydrolysis of extracellular nucleotides. This ecto enzyme, in tandem with CD73, therefore generates adenosine a newly recognized “immune checkpoint mediator” that interferes with anti-tumor immune responses. This talk will focus on CD39 and related ecto enzymes of the ENTPD family and encompass biochemistry and functionality on immune, stromal and vascular cells. Effects of CD39 inhibition in preclinical, experimental studies will be discussed. The proposed clinical application of purinergic therapies will be addressed; and be inclusive of suggestions on how these new approaches might develop in combination with other more established anti-cancer modalities.