@article{197e4104129e49afb11594e60e56688a,
title = "Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification",
abstract = "Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAMhi lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.",
keywords = "CITEseq, NSCLC, dendritic cells, high dimensional profiling, immunotherapy, macrophages, tumor cell atlas, tumor microenvironment, tumor mutational burden, tumor-associated myeloid cells",
author = "Leader, {Andrew M.} and Grout, {John A.} and Maier, {Barbara B.} and Nabet, {Barzin Y.} and Park, {Matthew D.} and Alexandra Tabachnikova and Christie Chang and Laura Walker and Alona Lansky and {Le Berichel}, Jessica and Leanna Troncoso and Nausicaa Malissen and Melanie Davila and Martin, {Jerome C.} and Giuliana Magri and Kevin Tuballes and Zhen Zhao and Francesca Petralia and Robert Samstein and D'Amore, {Natalie Roy} and Gavin Thurston and Kamphorst, {Alice O.} and Andrea Wolf and Raja Flores and Pei Wang and S{\"o}ren M{\"u}ller and Ira Mellman and Beasley, {Mary Beth} and H{\'e}l{\`e}ne Salmon and Rahman, {Adeeb H.} and Marron, {Thomas U.} and Ephraim Kenigsberg and Miriam Merad",
note = "Funding Information: Research support for this work was provided by Regeneron and Takeda . B.Y.N., S.M., and I.M. are employees and hold stock from Roche/Genentech. N.R.D. is an employee of Takeda. G.T. is an employee and holds stock from Regeneron. M.M. serves on the scientific advisory board and holds stock from Compugen Inc., Innate Pharma Inc., Morphic Therapeutic Inc., Myeloid Therapeutics Inc., Asher Bio Inc., Dren Bio Inc., Genenta Inc., and Nirogy Inc. M.M. receives funding from Genentech Inc. , Regeneron Inc. , Boehringer Ingelheim Inc. , and Takeda Inc . Funding Information: M.M. was supported by U24 AI118644-05S1, R01CA257195, R01CA254104 (Tumor macs), and Samuel Waxman Cancer Research Foundation. A.M.L. was supported by National Institutes of Health (NIH) grant 5T32CA078207; F.P. and P.W. by NIH U24 CA210993; N.M. by Fondation pour la Recherche M{\'e}dicale (FRMSPE201803005095) and College des Enseignants en Dermatologie de France. We thank A. Magen, P. Hamon, and M. Casanova-Acebes for critical comments on the manuscript, B. Greenbaum for helpful discussion, and the Mount Sinai Flow Cytometry Core, Human Immune Monitoring Center, Biorepository, and Scientific Computing team for resources and support. Data in this paper were used in a dissertation as partial fulfillment of the requirements for a PhD degree at the Graduate School of Biomedical Sciences at Mount Sinai. Data used in this publication were generated by the TCGA Research Network and the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium. Research support was provided by Regeneron and Takeda. The POPLAR study and related assays were funded and performed by Genentech. We recognize the patients and their families for their important contributions and sacrifices. M.M. and E.K. conceived the project. A.M.L. A.H.R. and M.M. designed the experiments. A.M.L. E.K. and M.M. wrote the manuscript. A.M.L. E.K. B.Y.N. M.D. and M.D.P. performed computational analysis. T.U.M. M.B.B. A.W. and R.F. facilitated access to human samples. A.M.L. J.A.G. C.C. B.B.M. A.T. L.W. L.T. J.L.B. N.M. G.M. and K.T. performed experiments. N.R.D. and G.T. funded part of the study. A.L. conducted patient consents and facilitated regulatory items. J.A.G. J.C.M. G.M. Z.Z. F.P. R.S. A.O.K. P.W. H.S. S.M. I.M. and T.U.M. provided further intellectual input. Research support for this work was provided by Regeneron and Takeda. B.Y.N. S.M. and I.M. are employees and hold stock from Roche/Genentech. N.R.D. is an employee of Takeda. G.T. is an employee and holds stock from Regeneron. M.M. serves on the scientific advisory board and holds stock from Compugen Inc. Innate Pharma Inc. Morphic Therapeutic Inc. Myeloid Therapeutics Inc. Asher Bio Inc. Dren Bio Inc. Genenta Inc. and Nirogy Inc. M.M. receives funding from Genentech Inc., Regeneron Inc., Boehringer Ingelheim Inc., and Takeda Inc. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Funding Information: M.M. was supported by U24 AI118644-05S1 , R01CA257195 , R01CA254104 ( Tumor macs ), and Samuel Waxman Cancer Research Foundation . A.M.L. was supported by National Institutes of Health (NIH) grant 5T32CA078207 ; F.P. and P.W. by NIH U24 CA210993; N.M. by Fondation pour la Recherche M{\'e}dicale ( FRMSPE201803005095 ) and College des Enseignants en Dermatologie de France . We thank A. Magen, P. Hamon, and M. Casanova-Acebes for critical comments on the manuscript, B. Greenbaum for helpful discussion, and the Mount Sinai Flow Cytometry Core, Human Immune Monitoring Center, Biorepository, and Scientific Computing team for resources and support. Data in this paper were used in a dissertation as partial fulfillment of the requirements for a PhD degree at the Graduate School of Biomedical Sciences at Mount Sinai. Data used in this publication were generated by the TCGA Research Network and the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium . Research support was provided by Regeneron and Takeda . The POPLAR study and related assays were funded and performed by Genentech . We recognize the patients and their families for their important contributions and sacrifices. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = dec,
day = "13",
doi = "10.1016/j.ccell.2021.10.009",
language = "English",
volume = "39",
pages = "1594--1609.e12",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "12",
}