Exosomal PD-L1 Mediates Tumor Immunosuppression
Abstract
Scientific Objective and Rationale of the Project: This proposal aims for the development of novel treatment monitoring strategies for the deadliest of all skin cancers, melanoma. The disease is generally caused by excessive ultraviolet light (sun) exposure. Once the tumor cells have spread from the skin to other organs, there is only a ~15% chance of more than 5 years of survival. Recently, a major breakthrough in cancer treatment is the development of the so-called “immune checkpoint blockade therapy,” which has shown remarkable promise in the treatment of melanoma. However, not all patients respond to immune checkpoint blockade therapies, and the responses are often partial or short-lived. A better understanding of the mechanism by which tumor cells evade the immune system is urgently needed to improve the efficacy of immune checkpoint blockade therapies. The core of our proposal is to study a novel mechanism on how melanoma cells secrete small vesicles (“exosomes”) that carry bioactive molecules to suppress immune system systemically, and to develop a new clinical test that may be used to monitor patient response to immunotherapy. In addition to a better understanding of how melanoma cells evade immune system, we also aim to developing a blood-based assay to predict whether patient will respond to the current immune therapy as early as 3-6 weeks into treatment. This assay may allow those patients who are not responding to this expensive treatment switch to alternative therapies without delay. We will take advantage of a clinical trial (ClinicalTrials.gov Identifier: NCT02434354) that is currently ongoing at Penn, and collaborate with a team of medical oncologists to address the proposed questions. Applicability of Research: Besides melanoma, immune checkpoint blockade therapy has also been applied to other cancers such as lung cancer and oral cancer. This makes checkpoint inhibitors the most promising drugs in current battles against cancers. Melanoma has historically been at the frontline for the development of new drugs to reinvigorate patient immune system to kill cancer. This proposal is designed to study a novel mechanism on how melanoma cells inhibit immune system systemically and to develop a new blood-based assay that can monitor patient response to immune therapy. Such an assay may allow oncologists to stratify on treatment patients at earlier time points of the therapy. Our studies will likely provide reliable biomarkers to inform clinicians on the choice of effective therapies, when the tumors are more likely to respond to other treatment options. This will increase the percentage of long-term survivors of melanoma. We expect that melanoma no longer remains a frightening cancer, but rather a condition we can “live with” for prolonged periods of time. Benefit for Active Duty Service and Their Families or Other Military Beneficiaries: It is highly expected that skin cancers including melanoma will dramatically increase as many military men and women are stationed in countries with intense sun exposure. Intermittent high sun exposure is the single most important factor for melanoma development and this cancer is increasingly being diagnosed in young (25 to 39 years of age) women. The outcome is often deadly. Our new treatment monitoring method could have a wide and immediate impact on the survivorship of military personnel with melanoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810289
Entities
People
- Xiaowei Xu
Organizations
- United States Army
- University of Pennsylvania