Your browser doesn't support javascript.
loading
Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.
Somasundaram, Rajasekharan; Connelly, Thomas; Choi, Robin; Choi, Hyeree; Samarkina, Anastasia; Li, Ling; Gregorio, Elizabeth; Chen, Yeqing; Thakur, Rohit; Abdel-Mohsen, Mohamed; Beqiri, Marilda; Kiernan, Meaghan; Perego, Michela; Wang, Fang; Xiao, Min; Brafford, Patricia; Yang, Xue; Xu, Xiaowei; Secreto, Anthony; Danet-Desnoyers, Gwenn; Traum, Daniel; Kaestner, Klaus H; Huang, Alexander C; Hristova, Denitsa; Wang, Joshua; Fukunaga-Kalabis, Mizuho; Krepler, Clemens; Ping-Chen, Fang; Zhou, Xiangyang; Gutierrez, Alexis; Rebecca, Vito W; Vonteddu, Prashanthi; Dotiwala, Farokh; Bala, Shashi; Majumdar, Sonali; Dweep, Harsh; Wickramasinghe, Jayamanna; Kossenkov, Andrew V; Reyes-Arbujas, Jorge; Santiago, Kenisha; Nguyen, Tran; Griss, Johannes; Keeney, Frederick; Hayden, James; Gavin, Brian J; Weiner, David; Montaner, Luis J; Liu, Qin; Peiffer, Lukas; Becker, Jürgen.
Afiliação
  • Somasundaram R; The Wistar Institute, Philadelphia, PA, USA. Shyam@wistar.org.
  • Connelly T; The Wistar Institute, Philadelphia, PA, USA.
  • Choi R; The Wistar Institute, Philadelphia, PA, USA.
  • Choi H; The Wistar Institute, Philadelphia, PA, USA.
  • Samarkina A; The Wistar Institute, Philadelphia, PA, USA.
  • Li L; The Wistar Institute, Philadelphia, PA, USA.
  • Gregorio E; The Wistar Institute, Philadelphia, PA, USA.
  • Chen Y; The Wistar Institute, Philadelphia, PA, USA.
  • Thakur R; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Abdel-Mohsen M; The Wistar Institute, Philadelphia, PA, USA.
  • Beqiri M; The Wistar Institute, Philadelphia, PA, USA.
  • Kiernan M; The Wistar Institute, Philadelphia, PA, USA.
  • Perego M; The Wistar Institute, Philadelphia, PA, USA.
  • Wang F; The Wistar Institute, Philadelphia, PA, USA.
  • Xiao M; The Wistar Institute, Philadelphia, PA, USA.
  • Brafford P; The Wistar Institute, Philadelphia, PA, USA.
  • Yang X; The Wistar Institute, Philadelphia, PA, USA.
  • Xu X; Department of Pathology and Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Secreto A; Department of Medicine, Stem Cell and Xenograft Core, University of Pennsylvania, Philadelphia, PA, USA.
  • Danet-Desnoyers G; Department of Medicine, Stem Cell and Xenograft Core, University of Pennsylvania, Philadelphia, PA, USA.
  • Traum D; Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Kaestner KH; Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Huang AC; Department of Pathology and Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Hristova D; The Wistar Institute, Philadelphia, PA, USA.
  • Wang J; The Wistar Institute, Philadelphia, PA, USA.
  • Fukunaga-Kalabis M; The Wistar Institute, Philadelphia, PA, USA.
  • Krepler C; The Wistar Institute, Philadelphia, PA, USA.
  • Ping-Chen F; The Wistar Institute, Philadelphia, PA, USA.
  • Zhou X; The Wistar Institute, Philadelphia, PA, USA.
  • Gutierrez A; The Wistar Institute, Philadelphia, PA, USA.
  • Rebecca VW; The Wistar Institute, Philadelphia, PA, USA.
  • Vonteddu P; The Wistar Institute, Philadelphia, PA, USA.
  • Dotiwala F; The Wistar Institute, Philadelphia, PA, USA.
  • Bala S; The Wistar Institute, Philadelphia, PA, USA.
  • Majumdar S; The Wistar Institute, Philadelphia, PA, USA.
  • Dweep H; The Wistar Institute, Philadelphia, PA, USA.
  • Wickramasinghe J; The Wistar Institute, Philadelphia, PA, USA.
  • Kossenkov AV; The Wistar Institute, Philadelphia, PA, USA.
  • Reyes-Arbujas J; The Wistar Institute, Philadelphia, PA, USA.
  • Santiago K; The Wistar Institute, Philadelphia, PA, USA.
  • Nguyen T; The Wistar Institute, Philadelphia, PA, USA.
  • Griss J; Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • Keeney F; The Wistar Institute, Philadelphia, PA, USA.
  • Hayden J; The Wistar Institute, Philadelphia, PA, USA.
  • Gavin BJ; The Wistar Institute, Philadelphia, PA, USA.
  • Weiner D; The Wistar Institute, Philadelphia, PA, USA.
  • Montaner LJ; The Wistar Institute, Philadelphia, PA, USA.
  • Liu Q; The Wistar Institute, Philadelphia, PA, USA.
  • Peiffer L; University of Duisburg-Essen, Essen, Germany.
  • Becker J; University of Duisburg-Essen, Essen, Germany.
Nat Commun ; 12(1): 346, 2021 01 12.
Article em En | MEDLINE | ID: mdl-33436641
ABSTRACT
Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos do Interstício Tumoral / Resistencia a Medicamentos Antineoplásicos / Receptor de Morte Celular Programada 1 / Mastócitos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos do Interstício Tumoral / Resistencia a Medicamentos Antineoplásicos / Receptor de Morte Celular Programada 1 / Mastócitos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article