PD-1 receptor outside the main paradigm: tumour-intrinsic role and clinical implications for checkpoint blockade.

Blocking the inhibitory receptor PD-1 on antitumour T lymphocytes is the main rationale underlying the clinical successes of cancer immunotherapies with checkpoint inhibitor (CI) antibodies (Abs). Besides this main paradigm, there is recent evidence of unconventional and "ectopic" signalling pathways of PD-1, found to be expressed not only by lymphocytes but also by peculiar subsets of cancer cells. Several groups reported on the tumour-intrinsic role of PD-1 in multiple settings, including melanoma, hepatocellular, thyroid, lung, pancreatic and colorectal cancer. Its functional activity appears intriguing but is not yet conclusively clarified. The initial studies are, in fact, supporting either a pro-tumourigenic role involved in chemoresistance and disease relapse or, oppositely, tumour-suppressive functions. The implications connected to the therapeutic administration of PD-1 blocking Abs are, of course, potentially relevant, respectively inferring an anti-tumour activity contrasting PD-1+ tumourigenic cells or a pro-tumoural effect by tackling PD-1 tumour suppressive signalling. The progressive exploration and consideration of this new paradigm of tumour-intrinsic PD-1 signalling may improve the interpretation of the observed clinical effects by anti-PD-1 Abs, likely resulting from multiple cumulative activities, and might provide important bases for dedicated clinical studies that take into account such composite roles of PD-1.