A_2Ablockade enhances anti-metastatic immune responses

Abstract

The specific targeting of tumor-elicited immunosuppression is a promising strategy for the treatment of cancer. We have recently demonstrated that targeting the immunosuppressive pathway mediated by CD73-derived adenosine through the blockade of A2A/A2B adenosine receptors significantly reduced the metastatic potential of CD73+ breast carcinomas and melanomas via both immunological and non-immunological mechanisms.

Extracellular 5′‐nucleotidase (CD73) promotes human breast cancer cells growth through AKT/GSK‐3β/β‐catenin/cyclinD1 signaling pathway

“…Notably, in mutated cells, these events involve in malignant transformation and are considered as a source of tumorigenesis, progression and metastasis. Moreover, adenosine is one of the most important immunosuppressive regulatory molecules in the tumor microenvironment . CD73 was also considered as an immune regulatory molecule and a novel checkpoint inhibitor targets recently .…”

“…Moreover, adenosine is one of the most important immunosuppressive regulatory molecules in the tumor microenvironment. 6,22 CD73 was also considered as an immune regulatory molecule and a novel checkpoint inhibitor targets recently. [23][24][25] Besides its enzymatic function, CD73 also mediates cancer invasion and metastasis by interaction with extracellular matrix components, such as laminin and fibronectin.…”

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

“…T-cell function in prostate tumors can be severely attenuated, as evidenced by their inability to mediate cytotoxic function and secrete cytokines, and by the expression of exhaustion markers (12)(13). One of the most recently described immunosuppressive pathways involved in tumor progression is the CD73-adenosinergic pathway (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The CD73-adenosinergic pathway is driven by tissue hypoxia and soluble factors frequently found in the TME, including type I IFNs, TNFa, IL1b, TGFb, and Wnt activators.…”

“…Several studies, including from our group, have highlighted the importance of the CD73-adenosine axis in tumor immune escape (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Using a transgenic mouse model of prostate cancer (i.e., TRAMP mice), we recently demonstrated that CD73 deficiency is associated with a significant reduction in prostate tumor growth and increased infiltration of CD8 þ T cells (29).…”

Therapeutic blockade of Activin-A improves NK cell function and anti-tumor immunity

“…Several biological factors have been reported to directly suppress or limit NK cell function via a range of mechanisms in malignant diseases. These include tumor derived metabolites such as adenosine (Beavis et al, 2013a;Beavis et al, 2013b) or enzymes such as indoleamine 2,3-dioxygenase-1 (IDO1 or IDO) (Liu et al, 2010), upregulation of cytokine-inducible SH2-containing protein (CIS, encoded by Cish) (Delconte et al, 2016a), downregulation of anti-apoptotic Bcl2 and Mcl1 proteins (Huntington et al, 2007;Sathe et al, 2014;Viant et al, 2017), modulation of NKG2D expression (Raulet et al, 2013), expression of inhibitory receptors for MHC-I (Benson and Caligiuri, 2014;Rahim and Makrigiannis, 2015), and transforming growth factor beta (TGFb) Viel et al, 2016).…”