PROJECT SUMMARY/ABSTRACT: In 2021, 600,000 people are estimated to die in the US from metastatic disease; the leading cause of early death and poor quality of life in patients with a variety of cancers including melanoma, lung cancer, breast cancer, and head and neck cancer. Up to 50% of patients with lung cancer and melanoma are estimated to develop intracranial metastatic disease. Immune checkpoint inhibitor (ICI) therapy has revolutionized treatment of metastatic melanoma, head and neck cancer, and lung cancer by providing an alternative treatment option in end-stage disease and demonstrating effectiveness as a first line therapy. Effectiveness of ICI targeting PD- 1/PD-L1 axis has been associated with the expression of PD-L1 transmembrane protein on tumor cell surface and the presence of infiltrating lymphocytes (TILs) within the tumor. Tumors expressing low levels of PD-L1 have been found to have decreased response to ICI therapy as compared to tumors with high PD-L1 expression. Currently, PD-L1 levels are measured using immunohistochemistry (IHC), which require invasive biopsies that limit evaluation of the dynamic nature of PD-L1 expression and can cause sampling errors. Therefore, we aim to validate a non-invasive quantitative imaging method of whole tumors using a novel PD-L1 positron emission tomography (PET) tracer in patients with head and neck cancer who undergo resection of primary tumor and locoregional lymph node metastases thus providing an excellent model to perform correlative studies with IHC. We will extend the study to patients with brain metastases because there is a critical need for a non-invasive test for PD-L1 in this population, as biopsy of these lesions is rare. In our study, we will image patients with brain metastases, which are predominantly from lung cancer and melanoma, that are planned to undergo biopsy. The ultimate goal of our research is to validate quantitative PD-L1 PET imaging in determining PD-L1 expression within primary and metastatic cancer without the need for biopsy and identify parameters of PD-L1 quantitative PET that will allow its translation into clinical practice. This method can then be used to determine which patients may benefit from immunotherapy.