TY - JOUR
T1 - Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma
AU - Li, Hanjie
AU - van der Leun, Anne M.
AU - Yofe, Ido
AU - Lubling, Yaniv
AU - Gelbard-Solodkin, Dikla
AU - van Akkooi, Alexander C. J.
AU - van den Braber, Marlous
AU - Rozeman, Elisa A.
AU - Haanen, John B. A. G.
AU - Blank, Christian U.
AU - Horlings, Hugo M.
AU - David, Eyal
AU - Baran, Yael
AU - Bercovich, Akhiad
AU - Lifshitz, Aviezer
AU - Schumacher, Ton N.
AU - Tanay, Amos
AU - Amit, Ido
N1 - This study is funded by Merck KGaA, Darmstadt, Germany. We thank Stephanie Blankenstein for help with patient inclusion and acquisition of clinical data; Raquel Gomez and Jan Hudecek for assistance with the scanning of tissue slides and data analysis; Noa Godin for artwork; Daniela Thommen and the NKI- AVL flow cytometry facility for assistance with sorting and flow cytometric analyses; the NKI-AVL Core Facility Molecular Pathology and Biobanking for supplying and processing of NKI-AVL Biobank material; and members of the Schumacher, Tanay, and Amit labs for input on experiment design and analyses I.A. is supported by the Chan Zuckerberg Initiative (CZI), the HHMI International Scholar Award, the European Research Council Consolidator Grant (ERC-COG) 724471-HemTree2.0, an MRA Established Investigator Award (509044), and the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine. T.N.S. is supported by the KWF Queen Wilhelmina Award (NKI 2013-6122) and ERC AdG SENSIT. A.T. is supported by the ERC (scAssembly), the CZI, and the Flight Attendant Medical Research Institute (FAMRI). I.A. and A.T. are supported by Helen and Martin Kimmel awards for innovative investigation and by the SCA award of the Wolfson Foundation and Family Charitable Trust. H.L. is funded by the Marie Curie Individual Fellowship (EU project 746382-SCALTIE). I.Y. is funded by the Rising Tide Foundation. Raw and processed single-cell RNA sequencing data can be downloaded from EGA: EGAS00001003363 and NCBI GEO: GSE123139.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.Errata: Errata: We correct errors due to a mistake in the Monte Carlo code in Sec. II of our paper which represent the overlap 𝒪 and the ratio 𝒩 of the respective norms of the two states in Fig. 3(b). We show here the corrected plot Fig. 3(b). The conclusions of the results remain the same also with the new data. The decay factor values as mentioned after Eq. (22) in our paper are modified as follows. For the case of four quasielectrons, the decay coefficient is 𝜆=0.0263 for 𝒪 and 𝜆=0.0271 for 𝒩. For the case of two quasiholes and two quasielectrons, the decay coefficient is 𝜆=0.0416 for 𝒪 and 𝜆=0.0422 for 𝒩. We note that these corrections do not alter the conclusions of Sec. II and, hence, the conclusions of our paper remain the same. We thank B. Jaworowski for pointing out the mistakes which we have now corrected.
AB - Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.Errata: Errata: We correct errors due to a mistake in the Monte Carlo code in Sec. II of our paper which represent the overlap 𝒪 and the ratio 𝒩 of the respective norms of the two states in Fig. 3(b). We show here the corrected plot Fig. 3(b). The conclusions of the results remain the same also with the new data. The decay factor values as mentioned after Eq. (22) in our paper are modified as follows. For the case of four quasielectrons, the decay coefficient is 𝜆=0.0263 for 𝒪 and 𝜆=0.0271 for 𝒩. For the case of two quasiholes and two quasielectrons, the decay coefficient is 𝜆=0.0416 for 𝒪 and 𝜆=0.0422 for 𝒩. We note that these corrections do not alter the conclusions of Sec. II and, hence, the conclusions of our paper remain the same. We thank B. Jaworowski for pointing out the mistakes which we have now corrected.
UR - http://www.scopus.com/inward/record.url?scp=85061004091&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.11.043
DO - 10.1016/j.cell.2018.11.043
M3 - مقالة
C2 - 30595452
SN - 0092-8674
VL - 176
SP - 775-789.e18
JO - Cell
JF - Cell
IS - 4
ER -