Enhancing the efficacy of radiation by spatially restricting anti-TGFb treatment to the tumor

PROJECT SUMMARY/ABSTRACT Self-renewing stem-like CD8+ T cells (Tstem-like), defined by expression of transcription factor TCF1/LEF, dwell in lymphoid tissues and are critical for anti-tumor immune responses. The role of Tstem-like cells in local and distant radiation response has not been defined. Preliminary single-cell RNA sequencing data demonstrates Tstem-like cells expand to repopulate the tumor within 3 days of radiation. In our first Aim we will determine whether Tstem- like cells from the tumor-draining lymph node are required for radiation response. Radiation and Transforming growth factor beta (TGFβ) inhibition are a promising therapeutic combination. However, TGFβ has opposing effects in anti-tumor CD8+ T cell differentiation, supporting Tstem-like cells in the tumor-draining lymph node, while simultaneously promoting exhaustion of tumor-infiltrating CD8+ T cells. In Aims 2 and 3, we will test radiation with 2nd generation TGFβ targeting therapeutics that spatially restrict the activity to the tumor microenvironment and relatively spare the tumor-draining lymph node, to determine whether spatial restriction of TGFβ inhibition is able to preserve Tstem-like cells and thereby enhance the efficacy of combination therapy.