@article{c625b8c822a041f284a472ef2b84cfd9,
title = "Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma",
abstract = "To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two chest computed tomography (CT)-defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers, and solid density nodules contain invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are central at the preinvasive state. T cell-mediated immune suppression is initiated in preinvasive nodules and sustained with rising intensity through progression to invasive tumors. Reduced T cell infiltration of the cancer cell nests is more frequently associated with preinvasive cancers, possibly until tumor evolution leads to a durable, viable invasive phenotype accompanied by more varied and robust immune suppression. Upregulation of immune checkpoints occurs only in the invasive nodules. Throughout progression, an effector immune response is present but is effectively thwarted by the immune-suppressive elements.",
keywords = "CP: Cancer, CT scan density, GGO, Tregs, extracellular matrix, lung ground glass lesions, preinvasive lung adenocarcinoma, tumor microenvironment, Lung Neoplasms/pathology, Humans, Adenocarcinoma of Lung/genetics, Tumor Microenvironment, Neoplasm Invasiveness/pathology, Retrospective Studies, Adenocarcinoma/pathology",
author = "Altorki, {Nasser K.} and Borczuk, {Alain C.} and Sebron Harrison and Groner, {Lauren K.} and Bhavneet Bhinder and Vivek Mittal and Olivier Elemento and McGraw, {Timothy E.}",
note = "Funding Information: The project was supported in part by NCI UG3 CA244697 (N.K.A., A.C.B., V.M., O.E., and T.E.M.), the Yoram Cohen family foundation (N.K.A.), the Vicky and Jay Furhman family fund (N.K.A.), and the Weill Cornell Medicine Meyer Cancer Center (N.K.A. and T.E.M.). O.E. is also supported by UL1TR002384 , R01CA194547 , and LLS SCOR grants 180078–02 and 7021–20 . T.E.M. is also supported by DOD LC180227 . We thank Gary Koretzky (Cornell University), Niroshana Anandasabapathy (WCM), and Juan Cubillos-Ruiz (WCM) for helpful discussions and critical reading of the manuscript. We thank Murtaza Malbari for expert oversite of the project and Abu Nasar, J. Nathan Mynard, Cathy Spinelli, and Joyce Gakuria for clinical database management. The WCM genomics core facility was used for RNA and DNA sequencing. The multiplex immunofluorescence (IF) was performed by Neogenomics Laboratories, Inc. (Fort Meyers, FL, USA) on a fee-for-service basis. Funding Information: N.K.A. has equity in Angiocrine Bioscience, TMRW, and View Point Medical. O.E. is supported by Janssen, J&J, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is a scientific advisor and an equity holder in Freenome, Owkin, Volastra Therapeutics, and One Three Biotech and a paid scientific advisor to Champions Oncology. T.E.M. receives research funding from Janssen and from Pfizer, Inc. All other authors declare no competing interests. Funding Information: The project was supported in part by NCI UG3 CA244697 (N.K.A. A.C.B. V.M. O.E. and T.E.M.), the Yoram Cohen family foundation (N.K.A.), the Vicky and Jay Furhman family fund (N.K.A.), and the Weill Cornell Medicine Meyer Cancer Center (N.K.A. and T.E.M.). O.E. is also supported by UL1TR002384, R01CA194547, and LLS SCOR grants 180078?02 and 7021?20. T.E.M. is also supported by DOD LC180227. We thank Gary Koretzky (Cornell University), Niroshana Anandasabapathy (WCM), and Juan Cubillos-Ruiz (WCM) for helpful discussions and critical reading of the manuscript. We thank Murtaza Malbari for expert oversite of the project and Abu Nasar, J. Nathan Mynard, Cathy Spinelli, and Joyce Gakuria for clinical database management. The WCM genomics core facility was used for RNA and DNA sequencing. The multiplex immunofluorescence (IF) was performed by Neogenomics Laboratories, Inc. (Fort Meyers, FL, USA) on a fee-for-service basis. N.K.A. conceptualized the project, contributed to experimental design, performed analysis and interpretations, and wrote the manuscript. A.C.B. contributed to experimental design and data analyses and edited the manuscript. S.H. reviewed and scored the CT data. L.G. reviewed and scored the CT data. B.B. contributed to analyses of the RNA-seq data. V.M. contributed to experimental design and edited the manuscript. O.E. contributed to experimental design and edited the manuscript. T.E.M. conceptualized the project, contributed to experimental design, performed analysis and interpretation, and wrote the manuscript. N.K.A. has equity in Angiocrine Bioscience, TMRW, and View Point Medical. O.E. is supported by Janssen, J&J, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is a scientific advisor and an equity holder in Freenome, Owkin, Volastra Therapeutics, and One Three Biotech and a paid scientific advisor to Champions Oncology. T.E.M. receives research funding from Janssen and from Pfizer, Inc. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "5",
doi = "10.1016/j.celrep.2022.110639",
language = "English (US)",
volume = "39",
pages = "110639",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}