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Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.
Mahadevan, Navin R; Knelson, Erik H; Wolff, Jacquelyn O; Vajdi, Amir; Saigí, Maria; Campisi, Marco; Hong, Deli; Thai, Tran C; Piel, Brandon; Han, Saemi; Reinhold, Bruce B; Duke-Cohan, Jonathan S; Poitras, Michael J; Taus, Luke J; Lizotte, Patrick H; Portell, Andrew; Quadros, Victor; Santucci, Alison D; Murayama, Takahiko; Cañadas, Israel; Kitajima, Shunsuke; Akitsu, Aoi; Fridrikh, Maya; Watanabe, Hideo; Reardon, Brendan; Gokhale, Prafulla C; Paweletz, Cloud P; Awad, Mark M; Van Allen, Eliezer M; Lako, Ana; Wang, Xi-Tao; Chen, Benjamin; Hong, Fangxin; Sholl, Lynette M; Tolstorukov, Michael Y; Pfaff, Kathleen; Jänne, Pasi A; Gjini, Evisa; Edwards, Robin; Rodig, Scott; Reinherz, Ellis L; Oser, Matthew G; Barbie, David A.
Afiliação
  • Mahadevan NR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Knelson EH; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
  • Wolff JO; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Vajdi A; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Saigí M; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Campisi M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Hong D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Thai TC; Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy.
  • Piel B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Han S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Reinhold BB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Duke-Cohan JS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Poitras MJ; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Taus LJ; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Lizotte PH; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Portell A; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Quadros V; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Santucci AD; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Murayama T; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Cañadas I; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Kitajima S; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Akitsu A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Fridrikh M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Watanabe H; Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • Reardon B; Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • Gokhale PC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Paweletz CP; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Awad MM; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Van Allen EM; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Lako A; Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Wang XT; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Chen B; Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Hong F; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Sholl LM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Tolstorukov MY; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Pfaff K; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Jänne PA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Gjini E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Edwards R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Rodig S; Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.
  • Reinherz EL; Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.
  • Oser MG; Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.
  • Barbie DA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Cancer Discov ; 11(8): 1952-1969, 2021 08.
Article em En | MEDLINE | ID: mdl-33707236
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'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.This article is highlighted in the In This Issue feature, p. 1861.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Pequenas Células do Pulmão / Plasticidade Celular / Neoplasias Pulmonares Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Cancer Discov Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma de Pequenas Células do Pulmão / Plasticidade Celular / Neoplasias Pulmonares Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Cancer Discov Ano de publicação: 2021 Tipo de documento: Article