Checkpoint therapies such as aPD-1 and aCTLA-4 represent a paradigm shift in cancer therapy. Their success in previously terminal diagnoses such as metastatic melanoma, prompt two conclusions 1) that the immune system is a constitutive element of the body?s defense against neoplasia and 2) that the immune system is a targetable tool to treat disease. However, the successes of checkpoint therapy have not translated to pancreatic ductal adenocarcinoma (PDAC), which remains a deadly disease with fewer than 10% of patients surviving beyond 5 years9. This resistance to checkpoint therapies can be partly explained by a paucity of conventional dendritic cells (cDCs) within the PDAC tumor microenvironment (TME). cDCs are uniquely specialized for priming anti-tumor T cell responses, expanding a population of cytotoxic T lymphocytes (CTLs) that are the target of therapies such as aPD-1. To combat this deficit in cDCs, we have employed a novel strategy of treating with the cDC differentiation factor Flt3L to expand cDC numbers, and an agonistic antibody against CD40 (aCD40) to license cDCs, augmenting their cancer-antigen presentation capacity. Surprisingly, this dual therapy generates a synergistic increase in intra-tumoral cDCs and T cells, compared to either monotherapy alone. Additionally, this combination leads to disease stabilization and renewed responsiveness to radiation therapy. These promising observations lack a mechanistic explanation, as the method of action of either drug alone does not justify their combined phenotype. Through this proposal, I aim to elucidate the cellular pathways underlying the increased numbers of cDCs and T cells within the PDAC TME, which largely mediate the efficacy of aCD40 + Flt3L in PDAC. I hypothesize that the synergistic benefit of aCD40 + Flt3L is mediated through enhanced recruitment of cDCs to the PDAC microenvironment, enabling effective downstream priming and mobilization of a tumor specific T cell response. Preliminary data indicate that the expanded pool of tumor infiltrating CTLs assumes an exhausted-like profile, suggesting that aCD40 + Flt3L dual therapy may render PDAC sensitive to checkpoint therapies. Clarifying the mechanisms driving the improved outcomes in aCD40 + Flt3L treated PDAC, will help optimize future treatment protocols and spur translation of this therapy to the clinic. These proposed aims are highly aligned with my personal goal of becoming a physician-scientist specializing in immuno-oncology. I am confident that this proposal will provide me with the skills and experience needed to succeed as an independent investigator endeavoring to bring emerging immunotherapies from my lab to patients suffering from debilitating malignancies.
Emerging evidence illustrates that conventional dendritic cells (cDCs) are essential for anti-tumor immunity. This project will elucidate mechanisms underlying the synergistic efficacy of a cDC targeted dual immunotherapy (aCD40 + Flt3L) in preclinical models of pancreatic ductal adenocarcinoma (PDAC). These proposed studies will interrogate cellular interactions within the PDAC tumor microenvironment, which will help optimize future therapeutic design, enabling the translation of combined aCD40 + Flt3L into a clinical setting.
