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dc.creatorFernandez-Sanmamed, M. (Miguel)-
dc.creatorNie, X. (Xinxin)-
dc.creatorDesai, S. (Shruti)-
dc.creatorVillaroel-Espíndola, F. (Franz)-
dc.creatorBadri, T. (Ti)-
dc.creatorZhao, D. (Dejian)-
dc.creatorKim, A.W. (Anthony W.)-
dc.creatorJi, L. (Lan)-
dc.creatorZhang, T. (Tianxiang)-
dc.creatorQuinlan, E. (Edward)-
dc.creatorCheng, X. (Xiaoxiao)-
dc.creatorHan, X. (Xue)-
dc.creatorVesely, M.D. (Matthew D.)-
dc.creatorNassar, A.F. (Ala F.)-
dc.creatorSun, J. (Jingwei)-
dc.creatorZhang, Y. (Yu)-
dc.creatorKim, T.K. (Tae Kon)-
dc.creatorWang, J. (Jun)-
dc.creatorMelero, I. (Ignacio)-
dc.creatorHerbst, R.S. (Roy S.)-
dc.creatorSchalper, K.A. (Kurt A.)-
dc.creatorChen, L. (Lieping)-
dc.date.accessioned2021-09-09T13:48:02Z-
dc.date.available2021-09-09T13:48:02Z-
dc.date.issued2021-
dc.identifier.citationFernández de Sanmamed-Gutiérrez, M. (Miguel); Nie, X. X.; Desai, S. S.; et al. "A burned-out CD8(+) T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy". Cancer Discovery. 11 (7), 2021, 1700 - 1715es
dc.identifier.issn2159-8274-
dc.identifier.urihttps://hdl.handle.net/10171/61982-
dc.description.abstractSpecific mechanisms by which tumor-infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 patients with resectable and 35 patients with advanced non-small cell lung cancer (NSCLC). We identified a burned-out CD8(+) TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME) but not in adjacent nontumoral tissues. Ebo showed the highest expression of proliferation and activation markers but produced the lowest amount of IFN gamma and were the most apoptotic CD8(+) TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in patients with NSCLC. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance. SIGNIFICANCE: We identified a highly proliferative, overactivated, and apoptotic dysfunctional CD8(+) tumor-infiltrating subpopulation that is functionally distinct from previously described exhausted T cells. This population is expanded in lung cancer tissues in a PD-1/B7-H1-dependent manner, and its abundance is associated with resistance to cancer immunotherapy, thus becoming a potential tissue biomarker.-
dc.description.sponsorshipThis study was supported by the Mark Foundation for Cancer Research (19-029-MIA; R.S. Herbst and K.A. Schalper), Navi- gate Biopharma (K.A. Schalper), AstraZeneca (K.A. Schalper), Yale SPORE in Lung Cancer (P50CA196530; R.S. Herbst), Department of Defense–Lung Cancer Research Program (W81XWH-16-1-0160; K.A. Schalper), the National Institutes of Health (R03CA219603 and R37CA245154; K.A. Schalper), Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT1715; R.S. Herbst and K.A. Schalper), and a Stand Up To Cancer–American Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17; K.A. Schalper). Stand Up To Cancer is a division of the Entertain- ment Industry Foundation. The indicated Stand Up To Cancer grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. M.F. San- mamed is supported by a Miguel Servet contract (MS17/00196) and a grant from Instituto de Salud Carlos III, Fondo de Investigacion Sanitaria (PI19/00668). M.D. Vesely is supported by a Physician- Scientist Career Development Award from the Dermatology Foun- dation, a Dermatology Fellow Award from the Melanoma Research Alliance, and a grant from the National Center for Advancing Trans- lational Sciences (KL2 TR001862)-
dc.language.isoen-
dc.rightsinfo:eu-repo/semantics/openAccess-
dc.subjectLymphocytes-
dc.subjectLandscape-
dc.subjectApoptosis-
dc.subjectCD8+-
dc.titleA burned-out CD8(+) T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy-
dc.typeinfo:eu-repo/semantics/article-
dc.identifier.doi10.1158/2159-8290.CD-20-0962-
dadun.citation.endingPage1715-
dadun.citation.number7-
dadun.citation.publicationNameCancer Discovery-
dadun.citation.startingPage1700-
dadun.citation.volume11-

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