T cell Trafficking Into the Cold Tumor Immune Microenvironment

A. Objective: Our goal is to improve the efficacy of anti-cancer immunotherapy, a 2018 PRCRP Topic Area. Our proposed studies focus on the immune-inhibiting tumor microenvironment (TME) in a subset of soft-tissue sarcoma (STS) tumors called Synovial Sarcoma (SS) and Myxoid/ Round Cell Liposarcoma (MRCL) that affect all ages, including children, adolescents and young adults, another FY18 Topic Area. The prevalence of admission for STS in the military health system has been estimated at 1.7 cases per 100,000 per year, and some STS are presumed to be related to Veterans’ exposure to Agent Orange or other herbicides during military service, one of the FY18 Military Relevance Focus Areas.1,2 Long-term, our findings are likely to help advance effective immunotherapies for patients with many types of solid malignancies in which the TME commonly inhibits effective immune responses. Successful immunotherapies have the potential to address significant gaps in cancer treatment within the U.S. population, including military Service members and their beneficiaries, and perhaps especially Veterans, our other FY18 Focus Area. In the proposed project, we will examine T cell trafficking and function in the context of tumor, stroma, tumor associated macrophages (MΦ) and endothelium within an ex-vivo 3-dimensional organoid culture system 3,4 that includes microfluidics to model real-time trafficking from the vasculature into the tumor's interstitium. Our findings will likely support new, even more effective therapeutic strategies to manipulate the tumor immune microenvironment to increase delivery of tumor-specific T cells into immunologically cold tumors.