Modulation of Cold Sarcoma Microenvironments to Enable T Cells in Experimental Systems

We are trying to improve immunotherapy for patients with synovial sarcoma (SS) and myxoid/round cell liposar-coma (MRCL); these cancers “should” be ideal candidates for immunotherapy as they have uniquely high and consistent expression of the immunogenic target, NY-ESO-1. Indeed, NY-ESO-1-targeting vaccines and adoptive cellular therapy (ACT) can induce regression of these tumors, but these responses are rarely durable. Our data suggests that these are classic ‘cold’ tumors (labeled C5 in a recent analysis),5 with generally low mutation burdens, few infiltrating T cells, low expression of major histocompatibility (MHC) / human leukocyte antigen (HLA) molecules, and failure to respond to single-agent PD-1 checkpoint blockade. Most investigations on T cell targeting of tumor focus only on the relationship between tumor and T cells. However, T cells may impact all of the cells within the TME in ways highly relevant to immunotherapy. Here we propose a unique analysis of T cells transduced with high affinity T cell receptors (TCRs) within an organoid model possessing endothelial cell coated microfluidics, stromal cells, tumor and macrophages (MF). This is an entirely novel and potentially very powerful application of the organoid model, as it allows for analysis of all of the changing TME elements during immunotherapy.

The specific Aims of this proposal are:
Aim 1: Characterize changes in MF phenotype following transfer of NY-ESO-1 specific T cells into SS and MRCL organoid models.
Aim 2: Test whether cell type specific interferon gamma increases trafficking and function of NY-ESO-1 specific T cells in a model TME with precisely defined components.