Abstract 5503: Tumor-resilient T-cell signatures identify cellular therapy response biomarkers and reveal FIBP inhibition as an immunotherapy potentiator

Abstract

Abstract Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (Tumor-resilient T cell), a computational model and web server that utilizes single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as TGFβ, TRAIL, and PGE2. Analyzing transcriptomic data from pretreatment or pre-manufacture patient samples, Tres reliably predicts the clinical effectiveness of immune checkpoint blockade or adoptive cell transfer in melanoma, lung, and B-cell malignancies. Further, Tres identified FIBP as the top negative marker of tumor-resilient T cells across many cancers. FIBP knockouts in murine and human CD8 T cells significantly enhanced T-cell mediated cancer-killing and adoptive cell therapy by limiting cholesterol metabolism, which otherwise inhibits effector T-cell function. These results demonstrate Tres’s utility in identifying clinical biomarkers of T-cell effectiveness and potential therapeutic targets for enhancing immunotherapies in solid tumors. Citation Format: Peng Jiang, Yu Zhang. Tumor-resilient T-cell signatures identify cellular therapy response biomarkers and reveal FIBP inhibition as an immunotherapy potentiator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5503.