| Summary: | While cancer treatments have advanced for multiple cancers, pancreatic cancer remains a lethal cancer with few therapy options available. This is due to the inaccessibility of the tumor by surgical and thermal ablative means, high potential for chemoresistance and metastasis, and strongly immunosuppressive tumor microenvironment that makes new treatment measures ineffective in clinic. Irreversible electroporation (IRE) utilizes short, high voltage electrical pulses to form microlesions in cell membranes and induce cell death. While IRE has had significant impact in pancreatic cancer treatment in clinical trials, little is known on the biological and immunological effects of IRE on pancreatic cancer. By studying the effects of IRE on pancreatic tumor biology and the host immune system, I hypothesize I can identify potential combination therapy targets for IRE. I utilized in vitro, ex vivo, and in vivo animal models of both human and murine cancer to study the effects of IRE on pancreatic cancer progression and its potential for immunomodulation. My findings have shown that IRE can significantly delay cancer progression by inducing necroptosis in the tumor and altering the tumor microenvironment by increasing inflammatory signaling. IRE can also produce viable antigens for presentation to induce local and systemic immunosurveillance. However, these effects are limited by countering expression of programmed-cell death ligand 1 (PD-L1), a checkpoint protein that inhibits cytotoxic lymphocyte activity and allows the tumors to recur. The effects of IRE can therefore be expanded by multiple combination therapy approaches, such as chemotherapeutic application (potentially with nanoparticle packaging), PD-1/PD-L1 antibody immunotherapies, and small molecule inhibitors directed at tumor growth signaling that previously showed limited efficacy in clinic. === Doctor of Philosophy === While cancer treatments have advanced for multiple cancers, pancreatic cancer remains a lethal cancer with few therapy options available. This is due to limited surgical candidacy, resistance to chemotherapy, high potential for secondary tumor formation, and the cloaking of the tumor from the immune system that make new treatment measures ineffective in clinic. Irreversible electroporation (IRE) utilizes short, high voltage electrical pulses to form permanent pores in cell membranes and induce cell death. While IRE has had significant impact in pancreatic cancer treatment in clinical trials, little is known on how IRE affects pancreatic cancer biological or how it can alter the immune system. By studying the effects of IRE on pancreatic tumor biology and the host immune system, I hypothesize I can identify potential combination therapy targets for IRE. I utilized cell, tissue, and animal models of both human and mouse pancreatic cancer to study the effects of IRE on disease progression and its potential for inducing immune responses. My findings have shown that IRE can significantly delay cancer progression by inducing controlled inflammatory cell death in the tumor and altering the supportive cells populations in the tumor that allows for immune system recognition. IRE can also produce markers specific to the tumor for presentation to induce recognition of the primary tumor and secondary lesions in the body. However, these effects are limited by countering expression of programmed-cell death ligand 1 (PD-L1), a checkpoint protein that reduces immune cell activity and allows the tumors to recur. The effects of IRE can therefore be expanded by multiple combination therapy approaches, such as chemotherapeutic application (potentially with nanoparticle packaging), PD-1/PD-L1 antibody immunotherapies, and small molecule inhibitors directed at tumor growth signaling that previously showed limited efficacy in clinic.
|
|---|
