Abstract LB130: Gfi1 controls the formation of effector-like CD8 T cells during chronic infection and cancer

Abstract During chronic infection and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to exhausted effector-like cells. Generation of effector-like cells is essential for the control of chronic infections and cancers, albeit limited. However, the precise cues and mechanisms directing their formation and maintenance are incompletely understood. Here, we find that the transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells during chronic LCMV Clone 13 infection and tumor progression. Deletion of Gfi1 in T cells disrupts the chromatin accessibility and transcriptomic programs needed for the development of LCMV-specific exhausted CD8 T cells, diminishing the formation of effector-like and terminally exhausted (Term-Exh) cells while increasing progenitors and newly identified Ly108+CX3CR1+ cells. Ly108+CX3CR1+ cells have a distinct chromatin profile and represent a transitory subset between progenitor and effector-like/Term-Exh cells. Similarly, Gfi1 loss impairs the formation of terminally differentiated tumor-infiltrating CD8 T cells (CD8 TILs) from progenitors, decreases cytokine production in CD8 TILs, and renders tumor-bearing mice less responsive to anti-CTLA-4. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells. Citation Format: Lewis Zhichang Shi, Oluwagbemiga A. Ojo. Gfi1 controls the formation of effector-like CD8 T cells during chronic infection and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB130.