Targeting the Interferon-gamma Pathway to Overcome Resistance to Immune Checkpoint Inhibitors in Melanoma

Project: Research project

Project Details

Description

Prior to the introduction of immune checkpoint inhibitors (ICIs), patients with metastatic melanoma could expect a dismal prognosis, with an average five-year overall survival of less than 10%. Fortunately, ICIs have significantly improved our ability to control this disease. Tumor cells express abnormal proteins on their cell surface, which allow the immune system to recognize and kill cancer cells. However, many malignant cells have co-opted mechanisms, called immune checkpoints, which hide their abnormalities, preventing immune recognition and subsequent tumor cell destruction. In 2018, Drs. James Allison and Tasuku Honjo were awarded the Nobel Prize in Physiology or Medicine for the discovery of the immune checkpoints CTLA-4 and PD-1. These findings led to the development of ICIs, a class of medications that block these disguising mechanisms and restore the immune system’s ability to recognize and kill cancer cells. Often referred to as immunotherapy, ICIs have led to response rates in melanoma that have far surpassed those seen with chemotherapy. However, although initial response rates are positive, approximately 40-60% of melanoma patients never respond to ICIs and up to 40% of patients relapse after an initial response. Recent discoveries suggest that a substance called interferon-gamma (IFNγ) controls both the initial “good” immune response by ICIs against tumor cells and at the same time a different “bad” mechanism that suppresses the immune response, causing resistance to ICIs. Our preliminary work has identified a protein, ULK1, that is required specifically for the IFNγ-control of the “bad” resistance mechanisms to ICIs. Additionally, melanoma patients with high levels of ULK1 have reduced survival rates compared to patients with low ULK1 levels. Thus, targeting ULK1 might prevent or reverse non-response and relapse to ICIs in these patients. In this proposal, we seek to test whether blocking ULK1 will uncouple the negative effects of IFNγ from the positive effects, improving the efficacy of ICI therapy. This work is clinically significant, as identification and specific targeting of resistance mechanisms to ICI therapy may overcome one of the largest barriers in the successful treatment of melanoma.
StatusActive
Effective start/end date7/1/216/30/22

Funding

  • ASCO Cancer Foundation (Agmt 04/23/21)

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