Role of LILRB4 in Melanoma
Abstract
Novel targeted therapies and immune checkpoint blockade immunotherapies have been developed and have shifted the paradigm in melanoma treatment. However, only a portion of melanoma patients are benefited from these therapies. Approximately 40% to 50% of metastatic melanoma patients respond to antibody blockade of the CTLA4 and PD1/PDL1 immune checkpoints, but other patients fail to respond and autoimmune side effects are significant. A number of predictive biomarkers have been proposed but, in most cases, lack actionable targets to reverse resistance. The employment of targeted therapies, on the other hand, depend on the genetic mutation status of patients. For example, about 40% of patients are BRAF mutation positive, who are eligible for the treatment of BRAF and MEK inhibitors. Still, the resistance to targeted therapy remains a severe challenge. It would be ideal to identify novel molecular targets that lead to combination of immunotherapy and targeted therapy. The leukocyte Ig-like receptor subfamily B (LILRB) proteins are suggested to have dual concordant roles in tumor biology – as immune inhibitory molecules and as tumor-supporting factors. Compared to CTLA4 and PD-1, the current effective immunotherapeutic targets, LILRBs have a broader array of immune blocking and cancer supportive functions. Based on our preliminary results, we hypothesize that the expression and signaling of LILRBs in immunosuppressive cells in melanoma microenvironment and in certain melanoma cells support tumor development. To test this hypothesis, we will determine the expression and function of LILRBs in tumor supportive immune cells in melanoma patients, and also determine the expression and potential function of LILRBs in melanoma cells per se. Since extrinsic regulation of the expression of immune checkpoint molecules is critical to the interplay between immune cells and tumor, we will further determine how LILRB4 expression is transcriptionally regulated by extrinsic factors. Our study addresses Precursor Lesions, Melanomagenesis, Host Factors and the Tumor Microenvironment as well as Therapeutic Prevention (e.g., interruption of disease progression, recurrence), two of the Fiscal Year 2019 Melanoma Research Program Focus Areas. Our work will likely apply to all melanoma patients, especially those who are not suitable for, failed, or relapsed from the existing therapies. The potential risks may include over-activation of the patient immune system, but presumably lower than the existing immunotherapies. The study is conceptually and technically innovative. We will elucidate the molecular mechanisms for expression and function of LILRB4 in immunosuppressive monocytic cells and melanoma cells, and determine whether targeting LILRB4 is a valuable strategy for melanoma treatment. The success of study will lead to clinical trials that may combine immunotherapy and targeted therapy within 3 years after the award period.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010793
Entities
People
- Chengcheng Zhang
Organizations
- United States Army
- University of Texas Southwestern Medical Center