Monday, February 10, 2025
2/10/2025
PROJECT SUMMARY/ABSTRACT Head and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of immunosuppressive leukocyte populations. Nor have biomarkers kept pace with clinical indications for use of immunomodulatory therapies. Here, we address the gap in clinically applicable immune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immune cell populations, followed by the application of such tools for studying HNSCC survivorship. The FDA recently approved pembrolizumab with or without chemotherapy as a first-line treatment for metastatic, or unresectable recurrent disease, which is poised to dramatically increase the number of patients receiving immunotherapy for HNSCC, further underscoring the critical need to identify biomarkers of response to treatment, even before de facto issues of drug cost. Further, recent successful trials of immunomodulatory agents treating late stage HNSCC reveal that there is a crucial role for the immune system in disease survival and prognosis. To understand and quantify immune status, we propose to apply novel DNA methylation-based immune phenotyping biomarkers that will define the immune suppressive state and allow us to intensively study its relationship to immunotherapy treatment response in HNSCC. The proposed study will draw from two independent, comparable, prospectively collected patient cohorts at NCI-designated Comprehensive Cancer Centers. Results from single cell tracing approaches to follow clones of cells in-vivo in cancer patients showed dramatic evidence that the intrinsic ability to attract new immune cells to the tumor results in improved checkpoint blockade activity. This finding strongly supports our approach to identifying biomarkers of checkpoint blockade response through measures in the peripheral blood. As new immunotherapies are developed for HNSCC, it is crucial to mediate the effects of the host’s compromised immune system. The new generation of epigenetic techniques for immune profiling will provide biomarkers that are useful both in assessing immune status and in addressing mechanisms of immune modifiers.
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