Novel Strategies for Checkpoint Blockade Inhibition : Targeting CD 39 Ectonucleotidase and Correcting Aberrant Purinergic Signaling in Cancer

Immunotherapies are newly developing interventions that modify the patient’s immune system to fight cancer, by stimulating rejection-type processes and/or by blocking suppressive pathways. ATP can be released at high levels from malignant cells; particularly after injury caused by radiotherapy or chemotherapy. Extracellular ATP provokes inflammation by “purinergic signals” and promote anti-tumor responses. Many tumors are proficient at converting ATP into the product adenosine, through the expression of ectonucleotidases, such as CD39 and CD73 inter alia, on cancer cells, regulatory immune cells, scar tissue and the vasculature. Several tumor cells (e.g. hematological malignancies, lymphoproliferative disease and multiple myeloma) also express CD39 intrinsically. The nucleoside derivatives, such as adenosine, interfere with immune responses to the cancer by serving as a “checkpoint inhibitor”, act in concert with other immunosuppressive factors e.g. PD-1; and also promote tumor blood supply by “neoangiogenesis”. We have shown that mAb to CD39 or chemical inhibitors to block the phosphohydrolytic functions, impede extracellular ATP scavenging and prevent generation of the derivative adenosine. We are developing panels of innovative, monoclonal antibodies (mAb) and testing small molecule inhibitors to block CD39, to abrogate immunosuppressive T regulatory cell functionality and suppressive functions in vitro. These planned approaches to neutralize CD39 will also have major impacts on cancer angiogenesis, blocking neovascularization of tumors as modeled in vivo. Our approach has the potential to provide new checkpoint blockade inhibitors, substantively bolster immunostimulatory effects to cancer and serve as adjunctive treatments in settings of other immunomodulatory approaches, radiotherapy and/or chemotherapy. miRNAs at Cell-Cell Junctions: Role in Cancer and Implications for Therapy Panos Z. Anastasiadis*, Antonis Kourtidis, Jennifer M. Carr, Irene K. Yan, Tushar Patel and E. Aubrey Thompson Mayo Clinic Comprehensive Cancer Center, FL, USA Abstract Cell-cell junction formation at the apical zonula adherens (ZA) is critical for epithelial tissue development or maintenance and is perturbed during cancer progression. E-cadherin (Ecad) and p120 catenin (p120) are core components of the ZA in epithelial cells. Recently, a novel Ecad-p120 partner called PLEKHA7 was identified to support the integrity of the ZA. Here, we reveal that the ZA, via PLEKHA7, associates with the RNA interference (RNAi) machinery, to suppress pro-tumorigenic signaling via miRNAs. PLEKHA7 co-localizes and co-precipitates with a non-nuclear subset of the core microprocessor proteins DROSHA and DGCR8. In addition, PLEKHA7 associates with all the major RISC components, including Ago2, GW182 and PABPC1, at the ZA. Recruitment of DROSHA, DGCR8 and Ago2 to the ZA is PLEKHA7and p120/cadherin-dependent, J of Natural Products in Cancer Prevention and TherapyCell-cell junction formation at the apical zonula adherens (ZA) is critical for epithelial tissue development or maintenance and is perturbed during cancer progression. E-cadherin (Ecad) and p120 catenin (p120) are core components of the ZA in epithelial cells. Recently, a novel Ecad-p120 partner called PLEKHA7 was identified to support the integrity of the ZA. Here, we reveal that the ZA, via PLEKHA7, associates with the RNA interference (RNAi) machinery, to suppress pro-tumorigenic signaling via miRNAs. PLEKHA7 co-localizes and co-precipitates with a non-nuclear subset of the core microprocessor proteins DROSHA and DGCR8. In addition, PLEKHA7 associates with all the major RISC components, including Ago2, GW182 and PABPC1, at the ZA. Recruitment of DROSHA, DGCR8 and Ago2 to the ZA is PLEKHA7and p120/cadherin-dependent, J of Natural Products in Cancer Prevention and Therapy