Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine–prostaglandin E₂cooperation

Abstract

Introduction Emerging data suggest that human inducible Treg (Tr1) produce adenosine and prostaglandin E2 and that these factors cooperate in mediating immune suppression. Areas covered Human Tr1 present in human tumors or blood of cancer patients express ectonucleotidases, CD39 and/or CD73, hydrolyze ATP to adenosine and are COX-2+. Expression of CD39 and/or CD73 on human tumors favors expansion and suppressor functions of Tr1. Adenosine and PGE2 signal via A2AR and EP2R expressed on effector T (Teff) cells, suppressing their anti-tumor functions by a common mechanism involving up-regulation of cytosolic cAMP levels and PKA type I activation. The frequency and activity of circulating CD4+CD39+ and CD4+COX-2+ Treg subsets increase in advanced disease and also following oncologic therapies. Expert Opinion Pharmacologic blocking of adenosine/PGE2 collaboration provides a clinically-feasible strategy for disarming of Treg. Used in conjunction with conventional anti-cancer drugs or immune interventions, pharmacologic inhibitors could improve outcome of oncologic therapies.

Clinical Impact of Regulatory T cells (Treg) in Cancer and HIV

“…The frequency of CD39+ Treg and their suppressor function were found to be increased in patients with cancer [13], and tumor-infiltrating CD39+ Treg were more suppressive than those present in the peripheral circulation [18,41]. The CD39 blockade with small molecule pharmacologic inhibitors or CD39-specific antibodies significantly impairs suppressor functions of Treg [37,42]. Further, as previously reported, in TME, pro-tumor suppressor activities of Treg occur in cooperation with the PGE 2 pathway [37,43].…”

Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for ‘two-in-one’ cancer chemoimmunotherapeutics

“…Especially, Tr1 can produce both immunosuppressive adenosine and PGE2 in the tumor microenvironment, which ultimately cooperate additively in mediating the suppression of T cell-mediated anti-tumor immune effector mechanisms (Fig. 3) [17,18,118,119].…”

“…The adenosine-and/or PGE2-induced cAMP-dependent RI/ PKAI activation has emerged as a novel mechanism by which Tr1 execute their anti-tumor immune suppressive effects [17,18,120]. Yaqub et al [120,121] and Mandapathil et al [17,18] have done some excellent work in this area.…”

“…As will be described in more detail below, the increased RI/PKAI levels have long been implicated in neoplastic transformation and tumor growth [16]. Similarly, emerging experimental and pre-clinical data indicate that RI/PKAI may have a crucial, but yet to be fully appreciated, role in the negative regulation of anti-tumor immunity, thus contributing to tumor immunoescape [17][18][19][20][21]. The focus of current review, therefore, is to specifically discuss this dichotomous role of RI/PKAI in the tumor microenvironment, proposing it to be an attractive target for a new, single-targeted, 'two hit' cancer chemoimmunotherapeutic approach.…”

Presence and Quantity of COX-2 in Lymph Node Metastases of Patients with Head and Neck Cancer

“…Studies suggest that COX-2 contributes to tumor progression by modulating the immune system to reduce anti-tumor immune responses [14,15]. Also, it has been suggested to act on tumor cells by promoting their mitotic activity and subsequently aid the conversion of premalignancy to invasive tumors [16]. Further, COX-2 has been described to induce angiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblastic growth factor, and therefore promotes tumor angiogenesis, tumor cell migration, and the formation of local and distant metastases [17,18].…”