CCSG Pilot: Circulating Neutrophils-Tailored Cancer Biomarker Discovery and Therapy

Scientific Abstract Metastasis accounts for the majority of cancer-related mortality. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and has a high mortality rate owing to early metastasis, poor prognosis and a lack of targeted therapies. In addition, TNBC tends to be more common in women younger than age 40, and who are black. Therefore, there is an unmet need to discover novel therapies for TNBC. Recently, immune checkpoint inhibitors (ICIs) such as anti-PD1 have been approved for TNBC treatment. Unfortunately, the vast majority of TNBC patients do not benefit from this treatment, but experience financial burden imposed by these highly priced therapies. Emerging evidences indicate that neutrophil accumulation not only promotes TNBC metastasis but also is responsible for anti-PD1 resistance, making them attractive targets for cancer therapy. In our preliminary study, we found that a CD62Lneg circulating neutrophils (cNeus) subset with immunosuppressive function was accumulated in metastatic TNBC mouse models and cancer patients. Important, we found that high CD62Lneg cNeus correlates with worse response to anti-PD1 in cancer patients. Mechanistically, we identified a novel G-CSF-p38δ axis-mediated pathway in promoting CD62Lneg cNeus generation. Strikingly, we discovered a novel p38δ inhibitor (MAPK13-In-1) that significantly reduced CD62Lneg cNeus generation and tumor growth in G-CSF high-expressing TNBC models. Thus, we hypothesize that CD62Lneg cNeus can serve as a biomarker to predict response to ICI therapy, and therapeutic target to improve anti-PD1 efficacy. We will determine the correlation of CD62Lneg cNeus with patient’s response to anti-PD1 (Aim1) and develop therapeutic strategies by harnessing CD62Lneg cNeus to improve anti-PD1 efficacy in metastatic TNBC preclinical models (Aim 2). The success of this project will not only provide novel biomarker for better prediction of patients who will benefit from anti-PD1 treatment to avoid unnecessary treatment, but also lay a groundwork by targeting CD62Lneg cNeus to improve anti-PD1 efficacy in metastatic TNBC. We will work closely with the Markey Cancer Center (MCC) Community Impact Office (CIO) and patient advocates to disseminate our research findings and promote public awareness of the importance of cancer research. The Flow Cytometry, and Biostatistics and Bioinformatics Shared Resource Facilities will be used for performing proposed studies. The team includes PI and Dr. Jinpeng Liu from Molecular and Cellular Oncology (MCO) Program, and Dr. Zhonglin Hao from Translational Oncology Research Program.