@article{08365c0431174e2f883aee5ef0f36b25,
title = "Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity",
abstract = "Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC{\textquoteright}s intrinsic immunogenicity. Significance: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.",
author = "Mahadevan, {Navin R.} and Knelson, {Erik H.} and Wolff, {Jacquelyn O.} and Amir Vajdi and Maria Saig{\'i} and Marco Campisi and Deli Hong and Thai, {Tran C.} and Brandon Piel and Saemi Han and Reinhold, {Bruce B.} and Duke-Cohan, {Jonathan S.} and Poitras, {Michael J.} and Taus, {Luke J.} and Lizotte, {Patrick H.} and Andrew Portell and Victor Quadros and Santucci, {Alison D.} and Takahiko Murayama and Israel Ca{\~n}adas and Shunsuke Kitajima and Aoi Akitsu and Maya Fridrikh and Hideo Watanabe and Brendan Reardon and Gokhale, {Prafulla C.} and Paweletz, {Cloud P.} and Awad, {Mark M.} and {Van Allen}, {Eliezer M.} and Ana Lako and Wang, {Xi Tao} and Benjamin Chen and Fangxin Hong and Sholl, {Lynette M.} and Tolstorukov, {Michael Y.} and Kathleen Pfaff and J{\"a}nne, {Pasi A.} and Evisa Gjini and Robin Edwards and Scott Rodig and Reinherz, {Ellis L.} and Oser, {Matthew G.} and Barbie, {David A.}",
note = "Funding Information: We thank Jun Qi for reagents, as well as Marina Vivero and Maur-izio Zanetti for insightful discussions on this work. Additionally, we thank the BMS Translational Pathology Histology Core Laboratory for preparation of H&E and unstained slides and the Dana-Farber/ Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry service. This work was supported by NIH R01CA190294 (D.A. Barbie), the Parker Institute for Cancer Immunotherapy (D.A. Barbie, E.L. Reinherz), Dunkin Donuts Award (D.A. Barbie, E.L. Rein-herz), Schaubert Family Funds (D.A. Barbie), Gross-Loh Research Fellowship (E.H. Knelson), and BMS II-ON Funding (D.A. Barbie, S. Rodig). Additional funding was provided by NIH T32HL7627-35 and NIH T32CA251062 (N.R. Mahadevan), NCI-T32 CA009172 (E.H. Knelson), and NCI/NIH K08CA222657 (M.G. Oser); Damon Runyon Cancer Research Foundation Clinical Investigator Award (M.G. Oser); Kaplan Family Funds (M.G. Oser); MIT-POLITO grant BIOMODE; Compagnia di San Paolo, under the joint “Doctorate of Bioengineering and Medical-Surgical Sciences” of University of Turin and Politecnico di Torino (M. Campisi); and Fundaci{\'o}n CRIS contra el c{\'a}ncer Grant (M. Saigi). Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant NIH 5 P30 CA06516. Further, we thank the Sequencing Facility of the Department of Oncological Sciences at Icahn School of Medicine at Mount Sinai (ISMMS) for sequencing assistance. This work was supported in part through Tisch Cancer Institute at ISMMS and the computational resources and staff expertise provided by Scientific Computing at ISMMS. Research reported in this article was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Anika Adeni, Kesi Michael, and Arrien Bertram for assistance in obtaining patient specimens. We are grateful to Benjamin Ferland, Thomas Thayer, and Teri Bowman for technical assistance and Jen-nifer Largaespada and Hannah Cassatly for superior administrative assistance. We are grateful to Neal Lindeman, Lecia Sequist, Jim DeCaprio, Camille Kotton, Anna Farago, and Jacob Sands for invaluable mentoring throughout this project. Funding Information: We thank Jun Qi for reagents, as well as Marina Vivero and Maurizio Zanetti for insightful discussions on this work. Additionally, we thank the BMS Translational Pathology Histology Core Laboratory for preparation of H&E and unstained slides and the Dana-Farber/ Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry service. This work was supported by NIH R01CA190294 (D.A. Barbie), the Parker Institute for Cancer Immunotherapy (D.A. Barbie, E.L. Reinherz), Dunkin Donuts Award (D.A. Barbie, E.L. Reinherz), Schaubert Family Funds (D.A. Barbie), Gross-Loh Research Fellowship (E.H. Knelson), and BMS II-ON Funding (D.A. Barbie, S. Rodig). Additional funding was provided by NIH T32HL762735 and NIH T32CA251062 (N.R. Mahadevan), NCI-T32 CA009172 (E.H. Knelson), and NCI/NIH K08CA222657 (M.G. Oser); Damon Runyon Cancer Research Foundation Clinical Investigator Award (M.G. Oser); Kaplan Family Funds (M.G. Oser); MIT-POLITO grant BIOMODE; Compagnia di San Paolo, under the joint ?Doctorate of Bioengineering and Medical-Surgical Sciences? of University of Turin and Politecnico di Torino (M. Campisi); and Fundaci?n CRIS contra el c?ncer Grant (M. Saigi). Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant NIH 5 P30 CA06516. Further, we thank the Sequencing Facility of the Department of Oncological Sciences at Icahn School of Medicine at Mount Sinai (ISMMS) for sequencing assistance. This work was supported in part through Tisch Cancer Institute at ISMMS and the computational resources and staff expertise provided by Scientific Computing at ISMMS. Research reported in this article was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Anika Adeni, Kesi Michael, and Arrien Bertram for assistance in obtaining patient specimens. We are grateful to Benjamin Ferland, Thomas Thayer, and Teri Bowman for technical assistance and Jennifer Largaespada and Hannah Cassatly for superior administrative assistance. We are grateful to Neal Lindeman, Lecia Sequist, Jim DeCaprio, Camille Kotton, Anna Farago, and Jacob Sands for invaluable mentoring throughout this project. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = aug,
doi = "10.1158/2159-8290.CD-20-0913",
language = "English",
volume = "11",
pages = "1952--1969",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "8",
}