Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy

Amy J. Wisdom, Yvonne M. Mowery (), Cierra S. Hong, Jonathon E. Himes, Barzin Y. Nabet, Xiaodi Qin, Dadong Zhang, Lan Chen, Hélène Fradin, Rutulkumar Patel, Alex M. Bassil, Eric S. Muise, Daniel A. King, Eric S. Xu, David J. Carpenter, Collin L. Kent, Kimberly S. Smythe, Nerissa T. Williams, Lixia Luo, Yan Ma, Ash A. Alizadeh, Kouros Owzar, Maximilian Diehn, Todd Bradley and David G. Kirsch ()
Additional contact information
Amy J. Wisdom: Duke University Medical Center
Yvonne M. Mowery: Duke University Medical Center
Cierra S. Hong: Duke University Medical Center
Jonathon E. Himes: Duke University Medical Center
Barzin Y. Nabet: Stanford University
Xiaodi Qin: Duke Cancer Institute
Dadong Zhang: Duke Cancer Institute
Lan Chen: Merck & Co., Inc
Hélène Fradin: Duke Center for Genomic and Computational Biology
Rutulkumar Patel: Duke University Medical Center
Alex M. Bassil: Duke University Medical Center
Eric S. Muise: Merck & Co., Inc
Daniel A. King: Stanford University
Eric S. Xu: Duke University Medical Center
David J. Carpenter: Duke University Medical Center
Collin L. Kent: Duke University Medical Center
Kimberly S. Smythe: Fred Hutchinson Cancer Research Center
Nerissa T. Williams: Duke University Medical Center
Lixia Luo: Duke University Medical Center
Yan Ma: Duke University Medical Center
Ash A. Alizadeh: Stanford University
Kouros Owzar: Duke Cancer Institute
Maximilian Diehn: Stanford University
Todd Bradley: Duke University Medical Center
David G. Kirsch: Duke University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

Date: 2020
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DOI: 10.1038/s41467-020-19917-0

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