American Association for Cancer Research
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Supplemental Figure S1 from Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector Function in Tumor-Infiltrating CD8+ T Cells

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posted on 2023-04-03, 23:07 authored by Melissa M. Berrien-Elliott, Jinyun Yuan, Lauryn E. Swier, Stephanie R. Jackson, Collin L. Chen, Maureen J. Donlin, Ryan M. Teague

Heat map of 53 selected genes differentially expressed in tolerant versus immune CD8+ T cells.



Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T-cell–intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8+ T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8+ T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8+ T-cell effector differentiation under otherwise tolerizing conditions. Cancer Immunol Res; 3(2); 116–24. ©2014 AACR.

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