Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.
Adoptive Transfer
/ methods
Animals
Biomarkers, Tumor
/ blood
Bone Neoplasms
/ blood
Cytokines
/ blood
Cytotoxicity, Immunologic
Dog Diseases
/ blood
Dogs
Female
Follow-Up Studies
Granzymes
/ metabolism
Killer Cells, Natural
/ immunology
Male
Natural Cytotoxicity Triggering Receptor 1
/ metabolism
Osteosarcoma
/ blood
Palliative Care
/ methods
Progression-Free Survival
Transcriptome
/ immunology
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
12
11
2019
accepted:
04
02
2020
entrez:
22
2
2020
pubmed:
23
2
2020
medline:
6
5
2020
Statut:
epublish
Résumé
We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.
Identifiants
pubmed: 32084139
doi: 10.1371/journal.pone.0224775
pii: PONE-D-19-28856
pmc: PMC7034869
doi:
Substances chimiques
Biomarkers, Tumor
0
Cytokines
0
Natural Cytotoxicity Triggering Receptor 1
0
Granzymes
EC 3.4.21.-
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0224775Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL140921
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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