CCSG Pilot: Improving Anti-PD1 Therapy in Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) is a particular breast cancer subtype which lacks effective targeted therapies and often displays early metastasis, with a poor prognosis and short survival. Although immune checkpoint inhibitor (ICI)-based immunotherapies such as anti-PD1 have been approved as a novel treatment for TNBC, the vast majority of TNBC patients are resistant to this treatment. Thus, there is an unmet need for novel strategies to improve ICI-based immunotherapy in TNBC patients. Both clinical and preclinical studies have shown that accumulation of neutrophils is one of the top reasons for resistance to anti-PD1. However, neutrophils are heterogeneous population. Identifying which neutrophil subpopulation is associated with anti- PD1 resistance and understanding how they are generated are critical for developing strategies to specially target “harmful” neutrophils, thereby improving anti-PD1 efficacy. In our preliminary studies, we identified a previously unrecognized immature CD62Lneg circulating neutrophil (cNeu) subpopulation that is associated with both metastasis and the resistance to anti-PD1 in several TNBC models and cancer patients. Mechanistically, we found that high G-CSF expression in TNBC cells elicits an “emergency” granulopoiesis (EG) process, which induces the aberrant immature CD62Lneg cNeu accumulation, leading to the resistance to anti-PD1. Consequently, targeting EG via blocking G-CSF inhibited immature CD62Lneg cNeu accumulation and sensitized resistant-TNBC to anti-PD1. Thus, we hypothesize that high G-CSF expression in TNBC cells induces EG, leading to aberrant accumulation of immature CD62Lneg cNeus, that is associated with resistance to anti-PD1. We will test our hypothesis by defining the impact of G-CSF in EG, immature CD62Lneg cNeu accumulation and response to anti-PD1 in TNBC mouse models (Aim1) and explore the clinic relevance of G-CSF in anti-PD1 therapy in TNBC patients (Aim 2). The proposed studies will discover a novel mechanism for the resistance to anti-PD1, and provide a new strategy to improve anti-PD1 efficacy by targeting EG to specially block immunosuppressive neutrophil accumulation. Statement of translational relevance, collaborations, and shared resource facility usage This project is significant and has clinical ramifications, because it will not only provide a new strategy to improve anti-PD1 efficacy by targeting EG to specially block immunosuppressive neutrophil accumulation, but also identify G-CSF as a potential biomarker to assist better prediction of patient’s response to anti-PD1.The project will be accomplished through a multidisciplinary team including basic and clinical scientists with expertise on breast cancer and hematology (PI), bioinformatics and biostatistics (Dr. Jinpeng Liu) and breast cancer oncology (Dr. Emily Marcinkowski). The Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resource Facilities will be used in this project.