Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Robert H. Vonderheide

Second Advisor

Terri M. Laufer

Abstract

The clinical success of immune checkpoint blockade (ICB) therapies in recent years has been remarkable. Yet most cancer patients, including entire disease types, do not respond to these agents. Pancreatic ductal adenocarcinoma (PDAC) is a common and lethal disease that does not respond to ICB treatment. Here, we demonstrate that immune dysregulation in the KPC mouse model of PDAC is mediated by a T-cell priming deficiency that begins in the earliest stages of oncogenesis. Furthermore, we show that systemic administration of a CD40 agonist reverses this T-cell priming deficiency. CD40 agonist has been shown to drive intratumoral T-cell infiltration and confer ICB-responsiveness to PDAC. This combination CD40/ICB therapy depends on CD4+ T-cells in both primary and re-challenge models. We demonstrate using single-cell transcriptomics that CD40/ICB therapy depends on the chemokine CCL5, which is upregulated across a range of myeloid cells within the tumor. CCL5 mediates the intratumoral influx of CD4+ T-cells in response to treatment, and this influx depends upon CCR5. Together, these studies describe the immune dysregulation of an ICB-resistant cancer and provide mechanistic insight into a clinically promising strategy to reverse that dysregulation.

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