Abstract LB-282: Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway

CD73 is the major extracellular adenosine-generating ecto-59-nucleotidase (Nt5e) that metabolizes extracellular (e) AMP and generates immunosuppressive adenosine (eADO). Elevated CD73 expression is often exploited by tumors and other cellular constituents of the tumor microenvironment (TME) as a mechanism of immune evasion. Clinically, a high level of CD73 expression in the tumor microenvironment (TME) is linked to poor prognosis. Experimental evidence also demonstrates that host CD73 activity in both hematopoietic and non-hematopoietic compartments augments the suppressive milieu of the TME. Nevertheless, the identities of CD73-expressing non-hematopoietic cells and factors that regulate CD73 activity of these cells have yet to be clearly defined. Our recent results unravel that cancer associated fibroblasts (CAFs) constitute a crucial non-hematopoietic CD73 hi compartment in the TME of human colorectal cancer (CRC) and murine MC38 CRC and EG7 lymphoma ectopic models. Strikingly, the CD73 expression profile among cohorts of published human CRC and breast cancer patient data sets confirmed its significant positive association with that of CAF-related markers, both of which are negatively correlated with poor survival. Cellular and transcriptomic analyses of CAFs in the EG7 TME reveal that CD73 expression in CAFs increases progressively during tumor progression, associated with elevated tissue hypoxia. Mechanistically, we demonstrate that the progressive elevation of CD73 expression in CAFs during tumor progression is caused by elevated eADO in the TME, which is resulted by the hypoxia/necrosis-associated eATP release. Furthermore, this eADO/adenosingeric pathway-induced CD73 upregulation in CAFs is mostly mediated by activation of A 2 BR and downstream MAPK signaling, which exacerbates eADO accumulation and serves as a feedforward loop of re-enforcing the immunosuppressive TME. Our study demonstrated that clinically and experimentally, high level of CD73 expression in CAFs represents another crucial immune checkpoint in the TME. Targeted inactivation or blockade of A 2 BR signaling may serve as a new strategy to prevent or alleviate the initiation of the eADO-CD73-associated amplification of immunosuppression in the TME, thereby improving the outcome of immunotherapy. Citation Format: Miao Yu, Gang Guo, Lei Huang, Libin Deng, Roni Bollag, Andrew Mellor, Huidong Shi, Yan Cui. Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-282.