Manipulating Myeloid Cells to Promote Immunotherapy Efficacy of Pancreatic Ductal Adenocarcinoma
Abstract
Pancreatic cancer is a devastatingly lethal disease that is predicted to be the second leading cause of cancer-related deaths in the United States by 2030. Lethality of this disease is due to late diagnosis, early metastasis, and resistance to aggressive therapeutic regimens. Current treatments, including surgery and chemotherapy, offer limited survival benefits. Immunotherapy is an approach that manipulates the patients own immune system to recognize and attack cancer. This approach is transforming the standard of care for many advanced cancer patients. However, pancreatic cancer often fails to respond to current immunotherapies. Our laboratory has developed two novel immunotherapies that are demonstrating marked anti-cancer activity in highly aggressive preclinical pancreatic cancer animal models. Both of these therapies work through the activation of a specific immune cell type, T cells. Our studies show that T cells that can specifically recognize pancreatic cancer and accumulate in tumors and metastases, areas where chemotherapy often cannot reach. T cells kill pancreatic tumor cells in a specific manner while sparing normal healthy cells. They also remodel the tumor microenvironment, including altering cell composition. While our approaches are destined for the clinic, our preclinical studies have also revealed that, ultimately, the suppressive tumor microenvironment, which is a hallmark of pancreatic cancer, shuts T cell-mediated functions, including their ability to kill tumor-cells. Pancreatic cancer is unique because the majority of the tumor mass is not tumor cells. Instead, pancreatic cancer contains many different types of cells and their factors. The most frequent cell type found in pancreatic cancer is an immune cell type called macrophages. Our studies indicate macrophages interact with T cells in pancreatic cancer and these interactions may determine whether tumor cells are killed or evade T cell-mediated killing. Macrophages are phenotypically and functional heterogeneous and can originate from cells in the blood called monocytes. When monocytes infiltrate sites of inflammation, they can differentiate into different types of macrophages, with some functions that promote T cell immunity and some functions that suppress T cell immunity. Our preliminary data suggest that a dialogue between T cells and macrophages in pancreatic cancer determines the outcome of immunotherapy. Specifically, our studies suggest that T cells can change macrophage properties in the tumor from being pro-tumor to anti-tumor. Our studies will elucidate the underlying program that governs macrophage differentiation in pancreatic cancer and develop a strategy to manipulate this program to support immunotherapy efficacy. We will test the hypothesis that T cells influence macrophage fate in pancreatic cancer and modulating macrophage fate using novel targets that we have identified will increase the efficacy of immunotherapy. In Aim 1, we will investigate the dynamics and evolution of macrophage differentiation in pancreatic cancer. In Aim 2, we will determine whether targeting candidate macrophage suppressive genes safely increases the efficacy of immunotherapy. Our proposal addresses “New drug development targeted toward cancer sensitivity and resistance mechanisms including immune mechanisms of resistance” and “Development of pharmacological, immunological, or genetic interception approaches.” Innovation: This proposal is based on our novel findings that T cells alter intratumoral macrophages in pancreatic cancer. This is the first study to define monocyte fate (spatially, temporally, and genetically) in pancreatic cancer and will encompass the role of T cells in this process. We will uncover whether monocytes differentiate into pro-tumor or anti-tumor macrophages, and the extent this program is influenced by T cells. The novel approaches developed will instruct how to therapeutically target monocytes/mac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110525
Entities
People
- Ingunn M. Stromnes
Organizations
- United States Army
- University of Minnesota