PT  - JOURNAL ARTICLE
AU  - Berrien-Elliott, Melissa M.
AU  - Yuan, Jinyun
AU  - Swier, Lauryn E.
AU  - Jackson, Stephanie R.
AU  - Chen, Collin L.
AU  - Donlin, Maureen J.
AU  - Teague, Ryan M.
TI  - Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector Function in Tumor-Infiltrating CD8<sup>+</sup> T Cells
AID  - 10.1158/2326-6066.CIR-14-0159
DP  - 2015 Feb 01
TA  - Cancer Immunology Research
PG  - 116--124
VI  - 3
IP  - 2
4099  - http://cancerimmunolres.aacrjournals.org/content/3/2/116.short
4100  - http://cancerimmunolres.aacrjournals.org/content/3/2/116.full
SO  - Cancer Immunol Res2015 Feb 01; 3
AB  - 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.