Abstract 7042: Enhancing TCR T cell function in solid tumors through in vivo combinatorial screens and single-cell analysis

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Abstract The therapeutic potential of T cell therapies for treating solid tumors can be limited by intrinsic T cell exhaustion mechanisms and the suppressive tumor microenvironment. To better understand these challenges and identify genetic perturbations to enhance T cell functions, we developed in vivo exhaustion models and performed pooled CRISPR/Cas9-based screens with detailed characterization of T cell states through single cell RNA-sequencing (scRNA-seq). In vivo Xenograft exhaustion models were developed in the format of T cell receptor (TCR) T cells, with tumor cell lines expressing TCR-specific antigen (NY-ESO-1) respectively. Individual perturbations were introduced into T cells via non-viral editing and pooled before transferred into mice with established tumors of various sizes that provided continuous antigen exposure to drive exhaustion, while providing sufficient number of T cells from tumor and spleen tissues for scRNA-seq. The pooled CRISPR in vivo screens in human TCR T cells enabled us to evaluate T cell phenotypes resulting from gain-of-function, loss-of-function, or combinations of these modifications across a wide array of target genes. We identified known and previously uncharacterized combinatorial perturbations that were enriched or depleted and were associated with distinct transcriptional phenotypes over the course of chronic stimulation. This approach allows us to bridge the gaps in our understanding of how T cells can be reprogrammed to overcome exhaustion and function more effectively in the challenging environment of solid tumors. Citation Format: Dina Polyak, Jessica Fuhriman, Josephine Susanto, Allyson Merrell, Mandi Simon, Catherine Oh, Andrew Cordazo, David DeTomasso, Carla Tocchini, Vibhavari Sail, Eric Cui, Jeff Milush, Levi Gray-Rupp, Brendan Galvin, Christopher Murriel, Grace Zheng, Angela C. Boroughs, Pratiksha Thakore, Soyoung Oh, Jake Freimer, Bob Chen, Celine Eidenschenk, Emily Wheeler, Jacob Levine, Jan-Christian Huetter, Jill Schartner, Katie Geiger-Schuller, Orit Rozenblatt-Rosen, Sascha Rutz, Ira Mellman, W. Nicholas Haining. Enhancing TCR T cell function in solid tumors through in vivo combinatorial screens and single-cell analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7042.

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