Partner Awards
Grant title (if any)
Brown/LUNGevity Award to Understand Mechanisms of Resistance to Immunotherapy
Dwight Owen, MD, MSc
The Ohio State University
Columbus
OH
This project will investigate the role of cells called macrophages, key components of the immune system that have multiple functions, including immune surveillance within a unique communication pathway called hedgehog (Hh). The hedgehog signaling pathway is involved in cell growth and differentiation, as well as maintenance of stem cells and tissue repair. Disruption or inhibition of Hh can create an environment that is less favorable for survival of cancer cells, allowing a patient’s immune system to combat it more effectively. This research has the potential to benefit patients who have been diagnosed with NSCLC, who have not responded to current treatments including immunotherapy by boosting the body’s own defense mechanisms.
Research Summary
Lung cancer remains one of the most lethal types of cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for a majority of cases. The goal of our research is to better understand the relationship between certain immune cells called macrophages and NSCLC, and how this interaction contributes to the cancer's survival and resistance to treatment. The scientific premise of our project lies in investigating a unique communication pathway known as hedgehog signaling within these macrophages and determining how it impacts the immune system's ability to fight lung cancer. If successful, our research has the potential to benefit patients who have been diagnosed with NSCLC, particularly those who have not responded to current treatments including treatment with immune therapies. By disrupting the hedgehog signaling pathway in macrophages, we hope to create a tumor immune environment that is less favorable for cancer cell survival, allowing patients' immune systems to effectively combat the disease. This research can pave the way for innovative therapeutic approaches that boost the body's own defense mechanisms.
Technical Abstract
The prognosis for patients with metastatic non-small cell lung cancer (NSCLC) remains poor despite recent progress in immune checkpoint blockade (ICB) therapy. Thus, there is an urgent need to understand mechanisms for lung cancer immune evasion within the tumor microenvironment (TME) in order to develop more effective and durable strategies for treating lung cancer. Tumor associated macrophages (TAMs), a major component of the tumor stromal mass, generally display an anti-inflammatory phenotype and can facilitate tumor growth by promoting angiogenesis, invasion, and metastasis, as well as immune evasion. However, it remains largely undefined exactly how these TAMs regulate anti-tumor immune responses within the TME. Will test the hypothesis that hedgehog signaling in TAMs interferes with recruitment of CD8+ T cells to the TME through the following specific aims: 1) Investigate the role of Hh inhibition with anti-PD-L1 therapy in non-small cell lung cancer; 2) Study the impact of Hh inhibition on TAMs and changes within the TME. The objective of this project is to understand signals required for functional polarization of TAMs within the TME and its contributions to immune cell dysregulation and cancer progression, and whether combined Hh inhibition and ICB can overcome resistance to immunotherapy.