EARLY INTERCEPTION OF PANCREATIC DUCTAL ADENOCARCINOMA BY TARGETING THE DYNAMIC TME: MODULATION OF NOVEL MICRORNA TARGETS AND UTILIZATION OF COMBINATION IMMUNOTHERAPY
Chu, Nina J
MetadataShow full item record
Pancreatic ductal adenocarcinoma (PDA), or pancreatic cancer, is currently the fourth leading cause of cancer deaths in the United States, and is projected to become the second leading cause surpassing those caused by breast, prostate, and colorectal cancers by the year 2030. Surgical resection is the only cure for the disease; however, only 20% of patients are eligible for surgical resection at the time of diagnosis. A hallmark of PDA that mediates its poor prognosis is the desmoplastic stroma, a major component of PDA’s dynamic tumor microenvironment (TME) that renders PDA refractory to radiation and chemotherapies. PDA tumorigenesis is initiated, propagated, and maintained by the expression of driver mutation KRAS, making mutant KRAS an ideal target for early stage disease intervention. In addition to targeting neoplastic cells that express mutant KRAS, we must also target the recruited stromal compartment that is essential to PDA’s immunosuppressive, tumor-supportive TME. The fibro-inflammatory stromal matrix is comprised of cellular and acellular constituents that create a dense, non-permissive environment protecting the tumor from immune recognition and chemotherapeutic penetration. Therefore, combination therapies that target transformed cells and stromal components administered during early PDA development will be the most promising solution to this lethal disease. Our studies aimed to investigate and ultimately modulate the epigenetic and immune mediated mechanisms that contribute to early PDA development in order to intercept disease progression. By expression profiling premalignant lesions, we uncovered novel microRNAs (miRNAs) whose levels are upregulated as a result of mutant KRAS activation. We discovered that miR-21 and miR-224 propel epithelial cell transformation and stromal cell activation altering their functional phenotypes in the early PDA TME, and that by endogenously inhibiting these miRNAs certain WT phenotypes can be restored. We also investigated whether administration of a mutant KRAS-targeting vaccine in combination with immunomodulatory agents and checkpoint blockade can alter specific inhibitory immune pathways in the early TME to impede premalignant progression. Our results demonstrated that our combination vaccine-based therapy significantly reprograms the immunosuppressive TME by reducing the population of pro-carcinogenic T regulatory cells and expression of checkpoint molecules, leading to increased effector T cell activation, cytotoxic function, and generation of memory populations. The reprogramming achieved by our combination therapy successfully delayed the progression of premalignant lesions in our endogenous mouse model of PDA. Taken altogether, these studies reveal that the early PDA TME can be targeted on multiple levels, epigenetically and immunologically, in combination to intercept early disease development.