CCSG Pilot: Determining the Role of the Immune Response in Improving the Efficacy of Radiotherapy with Pharmacological Inhibition of PTP1b

ABSTRACT Melanoma is the 5th most diagnosed cancer in the United States. While highly treatable in early stages, the 5-year survival rate drops to only 35% for patients with distant metastases. Adaptive checkpoint blockade (e.g., nivolumab and ipilimumab) and pathway targeted therapies (e.g., dabrafenib/BRAFi and trametinib/MEKi for BRAF V600-mutated tumors) have improved survival, but many patients will either not respond or will later relapse, necessitating other forms of therapy. We recently identified an innate immune checkpoint utilized by multiple cancer types including melanoma, breast, pancreatic, and lung cancer, that limits the anti-tumor response during radiotherapy. By pharmacologically targeting PTP1b, a signaling intermediary downstream of immune suppressive Pros1:Mer signaling, tumor growth is reduced by ~80% in combination with radiotherapy in preclinical models. However, it is unclear whether systemic PTP1b inhibition elicits tumor-intrinsic repair defects and/or drives the anti-tumor immune response. To address the hypothesis that combination therapy-mediated tumor suppression is an immune driven response, we will 1) utilize the Flow Cytometry and Immune Monitoring Core Facility and the Markey Cancer Center Oncogenomics Shared Resource to perform single cell RNA sequencing (scRNAseq) to identify whether changes in gene expression occur in tumor, stromal, or immune compartments drive the tumor suppressive phenotype and 2) determine the role of the immune response in limiting metastatic progression using an immunodeficient mouse model. As multiple clinical trials have shown that PTP1b inhibitors have favorable safety profiles, it may be possible to combine radiotherapy with existing drugs to limit tumor progression in cancer patients. These studies may provide rationale for application to additional funding mechanisms and future clinical trials.