Dissecting how activated immunity reshapes the stromal TME of pancreatic ductal adenocarcinoma

Abstract public domain (NIH RePORTER)

Project Summary / Abstract Immunotherapy has been shown to be effective in several cancer types leading to enhancement in long-term survival in subsets of patients. However, there are no proven effective immunotherapeutic approaches for pancreatic ductal adenocarcinoma (PDAC)1. There are many reasons why PDAC tumors do not respond to checkpoint immunotherapy, including modest tumor immunogenicity and T cell infiltration. However, another major factor in immunotherapy failure is the immunosuppressive tumor microenvironment (TME) characteristic of PDAC. The PDAC microenvironment is characterized by a desmoplastic stroma that is composed of an extracellular matrix rich in collagen and cancer-associated fibroblasts (CAFs)2,3. Three major subsets have been identified, including myofibroblast-like CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). However, there is still no clear consensus on the role each CAF subtype plays in the TME. While the field supports the hypothesis that anti-tumor immunity is often blunted in highly fibrotic tumors, what is not well understood is how tumor-associated fibrosis is remodeled when anti-tumor immunity is activated by therapy and how this impacts tumor control. This is a critical gap in our understanding that likely limits the development of immunotherapies for PDAC. A second rationale for the lack of response to immunotherapy is a paucity of conventional dendritic cells (cDCs) in the PDAC TME11. cDCs are professional antigen presenting cells that take up, process, and present antigen to both initiate and sustain anti-tumor T cell responses12. In mice, our lab has shown that the combination of systemic FLT3L and αCD40 agonist antibodies (CD40/FLT3L) restore cDCs numbers and function and thus drive T cell-mediated tumor control in PDAC models11. In recent studies we have advanced this approach into PDAC patients (NCT04536077). Importantly, ECM and CAFs may play both immune-promoting and/or immune-suppressive roles during therapy. Herein, I will study the impact of activation of tumor immunity by CD40/FLT3L treatment on PDAC ECM dynamics and CAF functional phenotypes. I will determine if these changes in ECM and CAF phenotypes during immunotherapy stimulate or blunt activities of cDCs in sustaining T cell immunity. Understanding how extracellular matrix heterogeneity either biases or impairs successful antigen presentation in the tumor microenvironment will help design rational therapeutics that will hopefully enhance immunotherapeutic responses in PDAC. As an MD/PhD student, being involved in translational studies directly impacting patients with PDAC will allow me to interface with the clinical implementation of the type of cancer immunology-based science I want to perform as an independent investigator and physician-scientist.

Public health relevance public domain (NIH RePORTER)

Project Narrative Despite clear evidence that anti-tumor immunity is often blunted in highly fibrotic tumors, there is little known of how tumor-associated fibrosis is remodeled when anti-tumor immunity is activated by therapy and how this response in turn impacts tumor control. These proposed studies will interrogate how changes in extracellular matrix and cancer-associated fibroblast phenotypes during conventional dendritic cell (cDC) directed dual immunotherapy (CD40/FLT3) stimulate or blunt activities of cDCs in sustaining T cell immunity in pancreatic ductal adenocarcinoma (PDAC). Through the use of murine models and patient samples from an active clinical trial utilizing this treatment approach, we hope to better understand how extracellular matrix heterogeneity either biases or impairs successful antigen presentation in the in the tumor microenvironment to help design rational therapeutics that will enhance immunotherapeutic responses in PDAC.