128O Evolution of transcriptomic and epigenomic intra-tumor heterogeneity in high-grade serous ovarian cancer with chemotherapy

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Background: Tumor-infiltrating lymphocyte (TIL) therapy can elicit durable responses in advanced cancers.While it is established that response to TIL therapy relies in large part on the activity of CD8 + T cells, the intratumoral CD8 + T cell states that determine clinical efficacy remain unclear.To address this, we developed a refined scRNAseq analytical approach to uncover clinically relevant T cell phenotypes and leveraged this to identify novel mechanisms of response and non-response to TIL therapy. Methods:We performed paired single-cell RNA and TCR sequencing on TIL from tumor biopsies and matched TIL products from 13 patients undergoing TIL therapy (7 Responders (R) and 6 Non Responders (NR)).A high-resolution single-cell CD8 + T cell embedding space was defined from scRNAseq data using a refined scVAE model, and granular TIL states were subsequently annotated.Clonal tracking using TCR sequencing data assessed expansion dynamics of these states from the baseline tumor into the expanded TIL product, while IL-2 signaling and predicted tumorreactivity were defined using established gene expression signatures.Results: Using this refined embedding of single CD8 + T cell sequencing data, we resolved previously obscured dysfunctional and precursor states with high granularity.Importantly, this enabled the identification of two distinct groups among NR patients: one (NR-low) lacking tumor-reactive cells, and another (NR-high) enriched for terminally dysfunctional T cells with limited expansion capacity.In contrast, R patients exhibited a distinct CD25 + T cell state characterized by intermediate dysfunction, robust tumor reactivity, and preferential clonal expansion into the TIL product.This "goldilocks" state showed enhanced IL-2 signaling and arose clonally from a precursor dysfunctional population with transcriptional features of both selfrenewal and tissue residency.Conclusions: These findings offer mechanistic insight into the tumor-intrinsic mechanisms that underlie the efficacy of TIL therapy and highlight the IL-2 axis and CD25 + intermediate CD8 + T cell states as potential biomarkers for patient selection and future optimization strategies to improve TIL therapy.Clinical trial identification: NCT02278887.

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