Exosomes in Immunotherapy Resistance
Abstract
Lung cancer-related death is primarily due to drug resistance and metastasis. Standard of care, which includes surgery, chemotherapy, and radiation therapy, has not improved patient survival, and the 5-year survival rate is dismal and remains at <16%. Advances made in cancer biology and therapy have led to the development and testing of molecularly targeted therapies. However, occurrence of tumor heterogeneity results in only a subset of patients benefiting from these therapies. More recently, the discovery of immune checkpoint (ICP) proteins, and their role in suppressing the immune response in cancer patients has led to development of inhibitor against these immune checkpoint proteins. These inhibitors are called immune checkpoint inhibitors (ICPIs), and thus have revolutionized cancer immunotherapy. While patients receiving ICPIs initially respond to treatment, some of the patients develop resistance resulting in disease progression and death. However, how patients develop resistance to ICPIs is poorly understood. The net outcome is disease recurrence and metastasis culminating in death. Therefore, there is a desperate need for understanding the underlying resistance mechanisms by which tumor cells adapt to evade immunotherapy. In recent years, studies have identified cancer cells to produce and shed small cellular vesicular particles called “exosomes.” Studies show that the cancer-derived exosomes play a role in cancer growth, progression, and treatment resistance. Based on these reports, we speculate that the cancer-derived exosomes contribute to resistance to immunotherapy and propose conducting preclinical laboratory studies using lung cancer models. Undertaking the research study will directly addresses the “Understand mechanisms of resistance to treatment (primary and secondary)” Area of Emphasis for the Lung Cancer Research Program. It is anticipated that the results obtained upon completing the study will unravel a new mechanism of resistance to immunotherapy, leading to innovative approaches to circumvent resistance and translate to clinical testing within a period of 2 to 3 years. This will result in enabling clinicians to make quick treatment decisions, thereby offering alternate therapies and improving survival of patients diagnosed with lung cancer. Finally, the study will make a significant impact in the way we diagnose and treat lung cancer among Veterans, Service members, their dependents, and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910647
Entities
People
- Rajagopal Ramesh
Organizations
- United States Army
- University of Oklahoma Health Sciences Center