Wisdom et al. compared responses of murine transplant and primary autochthonous sarcomas to PD-1 blockade against radiation therapy (RT). While transplanted tumors responded to anti-PD-1 and RT, primary tumors did not, due to immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. Single cell analysis of immune cells, primarily myeloid and T cells, after treatment showed primary sarcomas resembled most human sarcomas that respond poorly to immunotherapy. Transplanted tumors had an immune profile with increased activated CD8+ T cells, similar to inflamed human sarcomas, which respond better to PD-1 blockade.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA. (2) Department of Radiation Oncology, Duke University Medical Center, Dur
Author Info: (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. Duke Cancer Institute, Durham, NC, 27708, USA. yvonne.mowery@duke.edu. (3) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA. (4) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA. (5) Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA. Department of Oncology Biomarker Development, Genentech, South San Francisco, CA, 94080, USA. (6) Duke Cancer Institute, Durham, NC, 27708, USA. (7) Duke Cancer Institute, Durham, NC, 27708, USA. (8) Merck & Co., Inc, Kenilworth, NJ, 07033, USA. (9) Duke Center for Genomic and Computational Biology, Durham, NC, 27708, USA. (10) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (11) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (12) Merck & Co., Inc, Kenilworth, NJ, 07033, USA. (13) Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA. Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. (14) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (15) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (16) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (17) Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. (18) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (19) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (20) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. (21) Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA. Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA. (22) Duke Cancer Institute, Durham, NC, 27708, USA. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA. (23) Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA. Department of Radiation Oncology, Stanford University, Stanford, CA, 94305, USA. (24) Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA. Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, 64108, USA. (25) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA. david.kirsch@duke.edu. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA. david.kirsch@duke.edu. Duke Cancer Institute, Durham, NC, 27708, USA. david.kirsch@duke.edu.
