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Abstract Tumor infiltrating CD8+ T lymphocytes (TILs) develop a state of exhaustion, become terminally exhausted (Ttex) and fail to control tumor growth through cytolytic activity. At an early stage, however, progenitors of exhausted (pTex) TILs are renewable and still reprogrammable, and can generate efficient cytolytic effector cells. pTex highly express stemness program genes. There is a high interest in understanding the mechanisms that control stemness and exhaustion programs of TILs. In the current study we investigated the consequences of the removal of the transcription factor (TF) BCL11B in TILs on the control of the stemness and exhaustion programs, their epigenetics landscape, and the impact on the pTex versus Ttex TIL status. Using scRNAseq, bulk RNAseq and epigenomics approaches, we positioned BCL11B upstream of essential TFs of the stemness and exhaustion programs, as well as of the cytolytic activity program. BCL11B-/- CD8+ TILs have increased stemness and elevated effector program, but reduced exhaustion, and they promoted a superior response compared to WT TILs, restricting tumor growth. Importantly, evaluation of BCL11B KO signature in patients with metastatic melanoma treated with check point inhibitors, show a more favorable response and survival in the patients with enriched BCL11B KO TIL signature. Thus these results indicate that BCL11B constitutes a promising target for therapeutic intervention in cancer cell therapies to sustain stemness, cytolytic activity and reduce exhaustion. Citation Format: Dorina Avram, Timothy Shaw, Shari Pilon-Thomas, Leonardo Silvane, Tomas Zelenka. Program and epigenetic control of stemness and exhaustion of tumor infiltrating CD8+ T lymphocyte abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB358.
Avram et al. (Fri,) studied this question.