Priming pancreatic ductal adenocarcinoma using blood thinners to sensitize the efficacy of checkpoint immunotherapy

项目总结:

Project Summary: Cancer and stromal cells co-exist within a complex microenvironment that is characterized by hypoxia, acidosis, and high interstitial pressure; all of which generate a physical barrier to T cells' infiltration. Thus, the efficacy of an immunotherapy depends on many vital factors, including the ability of the checkpoint inhibitor to perfuse and diffuse through the extracellular matrix (ECM), shuttle through the less perfused vessels or interstitia, attenuate the immunosuppressive microenvironment and finally, recognize cancer cells to kill. Pancreatic ductal adenocarcinomas (PDACs) are poorly responsive to both chemo- and immunotherapies, mainly because of the presence of dense stroma and absence of immunomodulatory T-cells and cytokines in the tumor microenvironment (TME). However, the use of stroma-reducing agents has not been successful because of the fact that depletion of stroma-producing myofibroblasts did not correlate with immunosuppression and survival rate in pancreatic cancers. Thus, there is an unmet need to identify new strategies that can sensitize the TME of PDAC and increase the efficiency of immune checkpoint inhibitors. A largely overlooked, but potentially dominant barrier to tumoral drug delivery, are the small clots that form within the tumor vasculature and interstitial space, called intratumoral clots. Intratumoral fibrin clots are common in the most solid tumors, where PDACs exhibit extensive fibrinogen and fibrin clots throughout the tumor stroma and surrounding of the tumor cells. However, the impact of intratumoral clots on blood perfusion and hypoxia and in dampening the anti-tumor immunity has been immensely underestimated. Furthermore, no strategies have been in use that can outmaneuver clot- induced immune-barriers although anticoagulants have long been used to treat thrombosis in cancer patients. We hypothesize that intratumoral clots act as a transport barrier and prime the PDACs to create a suppressive microenvironment that helps to escape immune surveillance. We also hypothesize that enhanced perfusion sue to anticoagulation can alleviate hypoxia and alter the PDAC TME into an immune-supportive one, which will also benefit the efficacy of immunotherapy. To test our hypothesis, we designed three specific aims: (1) To study the clinical and pre-clinical relevance of fibrin deposition on regulating PDAC immunosuppressive microenvironment and tumor progression in PDAC; (2) To test the effects of blood thinners on T cells and macrophages against PDAC subtypes, in vitro; and (3) To assess the ability of blood thinners in potentiating the efficacy of anti-PD-1 antibody when administered in combination with chemotherapy in KPC and humanized mice. Successful completion of this study will positively affect the development of new treatment strategy combining ‘off-the-shelf’ blood thinners and thrombolytic with existing checkpoint inhibitors for pancreatic tumors, which are unresponsive to immunotherapy.