ORCID

https://orcid.org/0000-0001-8299-7104

Date of Award

2-7-2024

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies. While immune checkpoint blockade (ICB) is effective in many solid cancers, it has not been effective in PDAC. Furthermore, clinical trials combining ICB with standard of care chemo- or radio-therapy (RT), which should be able to prime anti-tumor immunity and unlock ICB, have not been overwhelmingly successful. Thus, understanding the effect of RT on PDAC tumor immunity is critical to plan better combination treatment strategies for this highly recalcitrant cancer. To elucidate if RT can prime antigen specific T cell responses, we first looked at human PDAC resections. In our RT-treated human PDAC cohort, we found no increase in the number of tumor infiltrating T cells in the tumor stroma compared to a control group. Additionally, using genetically engineered PDAC model, the p48-Cre/LSL-KrasG12D/p53Flox/Flox/OVA-GFP+ (KPC-OG) mice, RT alone, despite inducing temporary tumor control, similarly did not prime new antigen specific T cell responses. These data suggest that RT gives us no evidence of T cell priming. We postulated that the unique PDAC tumor microenvironment (TME), which is characterized by a fibrotic desmoplastic stroma, might play a role in limiting RT-induced immune priming. To study the role of PDAC TME, we developed a 3D organoid co-culture system. We found fibroblasts and collagen work synergistically to mitigate RT efficacy, which is mediated in part through Focal Adhesion Kinase (FAK). In mice, FAK inhibitor (FAKi) rescued RT resistance leading to significant tumor regression and enhanced survival. Associated with this regression, we found increased dendritic cells and tumor specific CD8+ T cells numbers. Single cell RNA seq and CyTOF revealed that the dual treatment primed immune cells and cancer associated fibroblasts to participate in better anti-tumor immunity in the form of enhanced antigen processing and presentation and T cell activation. This positive data prompted us to initiate a phase Ib study in which FAKi will be given in combination with RT to patients with locally advanced PDAC (NCT04331041). This clinical trial is currently underway with interesting early biomarker results, which mirrored our pre-clinical findings showing stromal reprogramming toward more anti-tumor phenotypes. Based on the anti-tumor changes brought by the dual treatment, we next hypothesized the combination of RT and FAKi would render ICB effective. Pre-clinical studies in mouse PDAC models showed that while RT and ICB was ineffective at tumor control, the triple combination of RT, FAKi, and ICB led to extended long-term survival. Overall, these data suggest that stromal modulation can be used to allow RT to prime anti-tumor immunity in PDAC and unlock ICB efficacy.

Language

English (en)

Chair and Committee

David G DeNardo

Committee Members

Gregory D Longmore, Robert D Schreiber, Julie K Schwarz, Sheila A Stewart

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