ORCID

http://orcid.org/0000-0001-6319-0372

Date of Award

Winter 12-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Pancreatic cancer carries a dismal prognosis, and desperately needs viable therapeutic interventions beyond chemo-radiation. T cell-dependent immunotherapies have shown great promise in several tumor types, but have not been effective for the vast majority of pancreatic cancer patients. This is, in part, due to our limited understanding of how antigenicity of pancreatic lesions is recognized, and how adaptive immunity is overcome in this disease. We sought to study tumor-immune interactions and identify mechanisms for this immune-failure using several spontaneous and unperturbed mouse models of pancreatic adenocarcinoma. We found that early pancreatic lesions fail to elicit tumor-limiting CD4+ TH1 and CD8+ T cell activity against a neoantigen, even though there is antigen recognition. Instead, the unique fibroinflammatory microenvironment favors the expansion of CD4+ TH17 T cells that are tumor-promoting. This is in contrast to similarly modeled lung adenocarcinoma; wherein early antigen-recognition is followed by favorable anti-tumor responses.We report that endogenous antigen-specific immunity in the pancreas is aberrant partly due to a scarcity of innate cells called conventional dendritic cells (cDCs). Restoring cDCs pharmacologically at an early stage in pancreatic tumorigenesis can rescue CD8+ T cell activity and limit tumor-promoting TH17 inflammation. Additionally, therapies targeting cDC infiltration and function in advanced pancreatic cancer can indirectly enhance CD8+ T cell and CD4+ TH1 activity to help control disease progression. Importantly, cDC-targeted therapy in established disease results in increased responsiveness to radiation therapy and immunotherapy in a T cell-dependent manner. These findings expand our understanding of T cell ineffectiveness in pancreatic cancer, clarifying why targeting T cells alone is insufficient in this disease context. Additionally, the results underscore the value of combinatorial strategies modulating cDCs to benefit existing therapies in pancreatic cancer and similar solid malignancies.

Language

English (en)

Chair and Committee

David G. DeNardo

Committee Members

Gregory D. Longmore, Jason C. Mills, Joshua B. Rubin, Robert D. Schreiber,

Comments

Permanent URL: https://doi.org/10.7936/tce3-c126

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