Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
03 01 2023
03 01 2023
Historique:
received:
09
12
2021
revised:
28
06
2022
accepted:
20
09
2022
pubmed:
27
9
2022
medline:
5
1
2023
entrez:
26
9
2022
Statut:
ppublish
Résumé
This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
Identifiants
pubmed: 36162051
pii: 711999
doi: 10.1158/1535-7163.MCT-21-0991
pmc: PMC9812921
mid: NIHMS1840527
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
112-122Subventions
Organisme : NCI NIH HHS
ID : U24 CA220245
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA168512
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196667
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197616
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG070149
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
Références
Phys Med Biol. 2018 Jan 09;63(2):025009
pubmed: 29148430
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Surg Oncol Clin N Am. 2016 Oct;25(4):621-43
pubmed: 27591490
Cancers (Basel). 2020 Nov 03;12(11):
pubmed: 33153100
Med Phys. 2011 Dec;38(12):6754-62
pubmed: 22149857
Lancet. 2002 Jun 29;359(9325):2235-41
pubmed: 12103287
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Bioinformatics. 2012 Jul 15;28(14):1811-7
pubmed: 22581179
J Exp Med. 2002 Jul 1;196(1):119-27
pubmed: 12093876
Clin Cancer Res. 2003 Jun;9(6):1941-56
pubmed: 12796356
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Lancet Oncol. 2017 Nov;18(11):1493-1501
pubmed: 28988646
J Clin Invest. 2013 Jul;123(7):2756-63
pubmed: 23863633
Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):203-9
pubmed: 19679403
Nat Genet. 2001 Dec;29(4):418-25
pubmed: 11694875
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
Nat Rev Drug Discov. 2019 Nov;18(12):899-900
pubmed: 31780841
Mamm Genome. 2018 Dec;29(11-12):843-865
pubmed: 30178305
J Clin Oncol. 1998 Jan;16(1):197-203
pubmed: 9440743
Nature. 2020 Jan;577(7791):556-560
pubmed: 31942077
Nat Med. 2007 Aug;13(8):992-7
pubmed: 17676052
JCI Insight. 2019 May 21;4(13):
pubmed: 31112524
Cell Rep. 2019 Sep 10;28(11):2837-2850.e5
pubmed: 31509746
N Engl J Med. 2015 Nov 12;373(20):1984
pubmed: 26559592
Tomography. 2021 Aug 07;7(3):358-372
pubmed: 34449750
Invasion Metastasis. 1986;6(1):44-57
pubmed: 3941028
J Clin Oncol. 2015 Jul 10;33(20):2231-8
pubmed: 25667281
PLoS One. 2020 Feb 25;15(2):e0225019
pubmed: 32097413
Science. 1974 Feb 8;183(4124):534-6
pubmed: 4588620
J Clin Invest. 2014 Oct;124(10):4305-19
pubmed: 25180607
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Oncoimmunology. 2019 Mar 16;8(5):e1577127
pubmed: 31069138
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
N Engl J Med. 2015 May 21;372(21):2018-28
pubmed: 25891174
Med Phys. 2004 Dec;31(12):3324-9
pubmed: 15651615
Sci Rep. 2017 Mar 06;7:43710
pubmed: 28262832
N Engl J Med. 2015 Oct 22;373(17):1627-39
pubmed: 26412456
Cancer Med. 2018 Sep;7(9):4228-4239
pubmed: 30030882
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Nat Commun. 2020 Dec 17;11(1):6410
pubmed: 33335088
Cancer Lett. 2015 Jan 1;356(1):82-90
pubmed: 24125863
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
Sci Rep. 2018 May 3;8(1):7012
pubmed: 29725089
Nat Immunol. 2004 Jan;5(1):3-4; author reply 4-5
pubmed: 14699396
Ann Surg Oncol. 2014 Aug;21(8):2484-9
pubmed: 24756814
J Clin Oncol. 1996 Mar;14(3):859-68
pubmed: 8622034
Nature. 2015 Apr 16;520(7547):373-7
pubmed: 25754329
N Engl J Med. 2015 Jul 2;373(1):23-34
pubmed: 26027431
PLoS One. 2019 Apr 8;14(4):e0207555
pubmed: 30958825
Nat Commun. 2017 Jul 10;8:15999
pubmed: 28691711
Cancer Discov. 2013 Oct;3(10):1190-205
pubmed: 23906982
Clin Cancer Res. 2016 Jul 1;22(13):3138-47
pubmed: 27154913
Front Oncol. 2012 Dec 17;2:191
pubmed: 23251903