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

Nat Commun. 2020 Dec 17;11(1):6410. doi: 10.1038/s41467-020-19917-0. | PubMed

Amy J Wisdom¹, Yvonne M Mowery^2,3, Cierra S Hong¹, Jonathon E Himes¹, Barzin Y Nabet^4,5, Xiaodi Qin⁶, Dadong Zhang⁶, Lan Chen⁷, Hélène Fradin⁸, Rutulkumar Patel⁹, Alex M Bassil⁹, Eric S Muise⁷, Daniel A King^4,10, Eric S Xu⁹, David J Carpenter⁹, Collin L Kent⁹, Kimberly S Smythe¹¹, Nerissa T Williams⁹, Lixia Luo⁹, Yan Ma⁹, Ash A Alizadeh^4,10,12, Kouros Owzar^6,13, Maximilian Diehn^4,12,14, Todd Bradley^15,16, David G Kirsch^17,18,19

1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA.
2. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. yvonne.mowery@duke.edu.
3. Duke Cancer Institute, Durham, NC, 27708, USA. yvonne.mowery@duke.edu.
4. Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.
5. Department of Oncology Biomarker Development, Genentech, South San Francisco, CA, 94080, USA.
6. Duke Cancer Institute, Durham, NC, 27708, USA.
7. Merck & Co., Inc, Kenilworth, NJ, 07033, USA.
8. Duke Center for Genomic and Computational Biology, Durham, NC, 27708, USA.
9. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA.
10. Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
11. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
12. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA.
13. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA.
14. Department of Radiation Oncology, Stanford University, Stanford, CA, 94305, USA.
15. Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
16. Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.
17. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA. david.kirsch@duke.edu.
18. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. david.kirsch@duke.edu.
19. Duke Cancer Institute, Durham, NC, 27708, USA. david.kirsch@duke.edu.

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.

Presented By Amy Wisdom | ORCID iD