Transformation of the Synovial Sarcoma Tumor Microenvironment from Cold to Hot to Enable Checkpoint Inhibition Therapy

Project: Research project

Project Details

Description

PD-1/PD-L1 immune checkpoint inhibitors have revolutionized oncology. Now, many cancer patients who would have rapidly died of their cancer enjoy durable remissions with excellent quality of life. Unfortunately, these therapies only benefit a minority of patients. We are studying a cancer of children, adolescents and young adults called synovial sarcoma. This is an immunologically "cold" tumor that is almost never controlled by PD-1 pathway inhibitors, despite consistent and homogenous expression of immunogenic antigens. Our
data suggest that systemic interferon gamma, an FDA approved drug, can transform the sarcoma microenvironment, making it "hot," with increased expression of antigen-presenting major histocompatibility complex (MHC) proteins and increased T cell infiltration, and increased PD-L1 expression on tumor. We hypothesize that interferon gamma thereby makes synovial sarcoma susceptible to PD-1 blockade. In the proposed project, we will combine interferon gamma and PD-1-blocking pembrolizumab in a clinical
trial aimed at eradicating synovial sarcoma. Tumor biopsies will be collected and multiplex immunohistochemistry performed to quantitate tumor MHC expression and T cell infiltrates, and to characterize other components of the tumor microenvironment that can determine the efficacy of immune responses. We
will use T cell receptor (TCR) sequencing to characterize T cell abundance and clonality. From some patients, single cell suspensions will be prepared for flow cytometry, gene expression analysis and single cell TCR/RNA
sequencing of sorted populations. We anticipate our findings will identify novel therapeutic targets and thereby inform subsequent trials that can help bring clinical benefit to more patients.
StatusActive
Effective start/end date7/15/2111/1/21

Funding

  • V Foundation for Cancer Research (T2018-006B)

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