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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Bone Marrow Transplantation
  • CD8-Positive T-Lymphocytes / immunology
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm / immunology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunotherapy
  • Mice, Inbred Strains
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Sarcoma / genetics
  • Sarcoma / immunology
  • Sarcoma / therapy*
  • Single-Cell Analysis / methods*
  • Tumor Escape
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*
  • Whole Exome Sequencing

Substances

  • Antineoplastic Agents, Immunological
  • DNA-Binding Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Rag2 protein, mouse

Associated data

  • figshare/10.6084/m9.figshare.5821263.v3