PET Imaging CD163+ Tumor Associated Macrophages in Head and Neck Cancer

Abstract public domain (NIH RePORTER)

Summary Inflammation predisposes the tumor microenvironment (TME) to the development of cancer and broadly promotes tumorigenesis. Cancer cells as well as surrounding stromal and inflammatory cells engage in carefully orchestrated, reciprocal interactions to form an inflammatory TME, which provides an essential ecological niche for cancer initiation and progression. Among the innate and adaptive immune cells recruited to the tumor site, tumor associated macrophages (TAMs) are an essential component of the TME and maintain a critical role in coordinating angiogenesis, extracellular matrix remodeling, cancer cell proliferation, metastasis, and immunosuppression, as well as driving resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, TAMs can mediate phagocytosis of cancer cells and cytotoxic tumor killing, and even engage in effective bidirectional interactions with components of the innate and adaptive immune system. As a result, TAMs have been widely explored as targets in cancer therapy. TAM targeted therapy in oncology requires a specific and quantitative measure of the spatiotemporal distribution of TAMs, preferably in a non-invasive manner such as positron emission tomography (PET). Such a tool will provide invaluable insight into the molecular and functional characteristics of the TME and how the immune response facilitates the progression of cancer or therapy response. Among the biomarkers for TAMs, CD163 is of particular interest due to its high and specific expression on TAMs and critical role in cancer pathogenesis. The level of CD163+ TAMs has been linked to poor prognosis, overall survival and metastasis of a range of malignancies including head and neck squamous cell carcinoma (HNSCC), lymphoma, glioma, pancreatic ductal adenocarcinoma. Moreover, the depletion of CD163+ TAMs not only led to the regression of tumors but also promoted anti-PD-1–resistant CD8+ cytotoxic T lymphocytes responses in mouse melanoma models, suggesting the potential of targeting CD163+ TAMs to reeducate tumor TME and promote antitumor immunity. Therefore, we proposed to use CD163 targeted PET radiotracer to determine the spatiotemporal distribution of CD163+ TAM upon tumor progression and upon treatment regimens to investigate its role in HNSCC pathogenesis. Currently, we have developed a CD163 targeted PET radiotracer showing sensitive and specific detection of CD163+ TAMs in mouse cardiovascular models and HNSCC models. To further promote the CD163 PET imaging from benchtop to clinical translation, we proposed the following three aims: Aim 1. Assess CD163+ TAMs dynamics in mouse HNSCC models following treatments. The use of animal models will provide unique and critical information about the immune cells’ variation before and after treatment, which will provide insights into evaluating the prognostic potential of CD163 PET in humans. The Aim 2. Translate CD163 targeted PET radiotracer in a Phase 0/Early Phase 1 trial; Aim 3. Assess the imaging characteristics of CD163 targeted PET radiotracer in HNSCC patients.

Public health relevance public domain (NIH RePORTER)

Project narrative Tumor associated macrophages (TAMs) are an essential component of the tumor microenvironment and play important role in tumor progression and treatment response. However, there is no clinical imaging agent to detect TAMs in vivo. Of various surface biomarkers expressed on TAMs, CD163 is closely associated with tumor progression and treatment response. Therefore, we have developed a targeted radiotracer to track CD163+ TAMs using positron emission tomography. In this proposal, we will first determine the CD163 targeted radiotracer to determine treatment response in mouse HNSCC models. We will then translate the radiotracer into humans and assess its potential for head and neck squamous cell carcinoma patient’s prognosis.