Uncovering and Targeting Molecular Mechanism(s) of Tumor-Intrinsic Immunotherapeutic Resistance in Melanoma
Abstract
Skin cancer is the most common type of cancer in the United States, outnumbering all other types of cancer combined. Melanoma is the deadliest form and accounts for the most deaths related to skin cancer. Prior to 2011, melanoma was claimed largely incurable, due to lack of effective treatments. In 2011, a new therapy called ipilimumab showed impressive clinical responses in patients with advanced melanoma, and the Food and Drug Administration (FDA) subsequently approved its use to treat melanoma. By blocking the negative signals that normally suppress patient’s own immune cells to combat cancer, ipilimumab reactivates these immune cells that track down and kill tumor cells. Over the past decade, more than 60 approvals have been given to similar therapies like ipilimumab, collectively known as immunotherapies. Nowadays, immunotherapies have become a mainstay of cancer treatment. However, despite the great successes of immunotherapies in melanoma, unfortunately, many patients have developed resistance to immunotherapies and the number of melanoma cases has been increasing. According to Skin Cancer Foundation, in 2021, there will be 106,110 newly diagnosed melanoma cases, among which 7,180 people will die from melanoma. By 2040, it is predicted that melanoma will surpass colorectal and lung cancers to become the second most common cancer type in the United States. Therefore, how to overcome therapeutic resistance to immunotherapies is of great significance and will certainly help improve melanoma control. As original efforts to first understand why most melanoma patients were resistant to immunotherapies, we conducted a systemic genetic analysis of melanoma samples treated with ipilimumab and found that those patients that did not respond to ipilimumab had melanomas harboring loss of the interferon-gamma signaling genes. Similar results were obtained from many other groups in other types of immunotherapies, highlighting the loss of the interferon-gamma signaling genes as a major mechanism of resistance to immunotherapies. To uncover targets that can be harnessed as effective therapeutic interventions, we conducted a series of studies using a mouse melanoma model lacking a functional interferon-gamma signaling. Our results revealed multiple interesting metabolic and molecular alterations. To our delight, by targeting one of such alterations, the constitutively active JAK1/2 with an inhibitor that has been approved by the FDA, Ruxolitinib, we showed in our preliminary experiments that it selectively suppressed the growth of melanomas that are resistant to immunotherapy. In-depth mechanistic studies revealed an essential role of T cells, the circulating immune warriors in our body, in mediating therapeutic effects of Ruxolitinib. Furthermore, the constitutive activation of JAK1/2 was under the regulation of a heightened metabolic process that breaks down glucose to provide energy and building blocks for tumor cells. Consequently, we found that melanomas resistant to immunotherapy were also highly sensitive to pharmacological inhibitors of this metabolic pathway. Our major goal in this application is to firmly establish that these metabolic and molecular abnormalities are the cause but not the consequence of therapeutic resistance to immunotherapy (Aim 1), and then to strategically target them to achieve optimal therapeutic outcomes, by not only killing tumor cells but also helping T cells to combat cancer (Aim 2). We would like to state that Aim 1, upon completion, will establish for the first time a causal relationship of metabolic reprogramming in tumor cells to therapeutic resistance to immunotherapy. We hope that systemic analyses in Aim 2 will identify key cellular and molecular mechanisms of how loss of interferon-gamma signaling in melanoma cells drives therapeutic resistance to immunotherapy; more importantly, since all of our tested compounds have already been approved or used clinically, we envi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210786
Entities
People
- Lewis Shi
Organizations
- United States Army
- University of Alabama at Birmingham