TY - JOUR
T1 - Checkpoint blockade immunotherapy relies on T-betbutnoteomes to induceeffector functionin tumor-infiltrating CD8+ T cells
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.
N1 - Funding Information:
Grant Support Research reportedinthis publication was supported by the National Institute of Allergy and Infectious Disease (R01AI087764) to R.M. Teague, by a Cancer Research Institute Investigator Award to R.M. Teague, and by a National Cancer Institute fellowship (F30CA180375) to S.R. Jackson.
Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/2
Y1 - 2015/2
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84962278566&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-14-0159
DO - 10.1158/2326-6066.CIR-14-0159
M3 - Article
C2 - 25516478
AN - SCOPUS:84962278566
VL - 3
SP - 116
EP - 124
JO - Cancer Immunology Research
JF - Cancer Immunology Research
SN - 2326-6066
IS - 2
ER -