Relieving Immune-Suppressive Pathways in Breast Cancer to Improve Outcomes
Abstract
Breast cancer (BC) remains the most common cancer among women worldwide. During the past decades, organized screening, early detection, and the development of targeted therapies impacting hormone receptor positive (HR+) and human epidermal growth factor receptor 2 (HER2) overexpressing tumors have decreased mortality rates. Triple-negative breast cancer (TNBC) represents the most aggressive subtype with a high risk of metastasis and recurrence and is associated with diminished long-term survival. Treatment options for TNBC are limited and rely on conventional chemotherapy and radiation, which are often inefficient to prevent metastasis and recurrence; thus, identifying efficacious targets for therapy and biomarkers that stratify patients with TNBC represents an urgent medical need. Previous research in the Coussens laboratory highlighted the fact that immune cells infiltrating the tumor microenvironment of BC is a key feature of cancer progression and represents a tractable target for therapy. The immune system can exert both pro- and anti-tumorigenic activities, whereas cytotoxic CD8+ T cells are involved in anti-tumor responses associated with better prognosis, tumor-associated macrophages (TAMs) on the other hand reciprocally blunt T cell cytotoxicity and are associated with worse outcomes. Notably, therapeutic targeting of biological pathways controlling TAM effector function improves responses to chemotherapy and increases survival of mice bearing TNBC-like mammary adenocarcinomas by enabling CD8+ T cell-dependent antitumor activity. Based on these preclinical data, we hypothesized that further addition of therapies releasing critical T cell checkpoints would further improve outcomes for tumor-bearing mice. Indeed, addition of critical checkpoint antagonist to mice treated with TAM-targeted and chemotherapy significantly improves survival for 60% of treated mice, associated with expansion of a specific population of short-lived CD8+ T resident memory cells. Based on these data, we hypothesize that further addition of anti-cancer agents that induce transcriptional reprograming of immune cells, e.g., histone deacetylase (HDAC) inhibitors, will further improve outcomes for mice by instilling durable anti-tumor CD8+ T cell cytotoxicity. While results from these studies can be rapidly translated to the clinic, they also provide a preclinical platform within which to identify biomarkers identifying mice poised to respond that can also be translated to the clinic and further impact outcomes for patients with BC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010007
Entities
People
- Amanda Poissonnier
Organizations
- Oregon Health & Science University
- United States Army