Canine osteosarcoma checkpoint expression correlates with metastasis and T-cell infiltrate
| Autor: | Michael J. Dark, Bikash Sahay, Marc E. Salute, Elizabeth M. Whitley, Elias Sayour, Lung-Ji Chang, Zachary Sandoval, Galaxia Cortés-Hinojosa, Duane Mitchell, Rowan J. Milner, Jonathan R. Cowart, Matthew Cascio |
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| Rok vydání: | 2019 |
| Předmět: |
Male
B7 Antigens 040301 veterinary sciences medicine.medical_treatment T cell T-Lymphocytes Immunology Blotting Western Bone Neoplasms Biology Real-Time Polymerase Chain Reaction Canine Osteosarcoma B7-H1 Antigen Flow cytometry Metastasis Cell Line 0403 veterinary science 03 medical and health sciences Immune system Dogs Lymphocytes Tumor-Infiltrating Antigens Neoplasm medicine Animals Humans Dog Diseases 030304 developmental biology 0303 health sciences Osteosarcoma General Veterinary medicine.diagnostic_test Tumor-infiltrating lymphocytes 04 agricultural and veterinary sciences Immunotherapy medicine.disease Flow Cytometry medicine.anatomical_structure Cancer research Female Receptors Tumor Necrosis Factor Member 14 |
| Zdroj: | Veterinary immunology and immunopathology. 232 |
| ISSN: | 1873-2534 |
| Popis: | Background Immune-targeted therapies are being successfully implemented into cancer clinical practice. In particular checkpoint inhibitors are employed to modulate the immune microenvironment of solid tumors. We sought to determine the expression of PD-L1, HVEM, and B7H3 in human and canine osteosarcoma, and correlate expression with clinical features and tumor infiltrating lymphocytes in naturally-occurring canine osteosarcoma. Methods Flow cytometry was used to measure ligand surface expression of five human and three canine cell lines. Immunohistochemistry was utilized for expression of ligands and lymphocyte markers in thirty-seven treatment-naive canine osteosarcoma patients. Results All cell lines expressed all three ligands at variable levels in both species. Metastatic lesions were associated with higher expression of all three ligands in patient tumor samples. PD-L1 expression strongly correlated with B7H3 and HVEM expression, while HVEM and B7H3 were weakly correlated. Whereas peritumoral T-cell expression positively correlated with PD-L1 and HVEM tumor expression, the presence of T-cells intratumorally were rare. Furthermore, intratumor penetration by T-cells was greatest in metastatic lesions, despite log-fold increases in peritumoral T-cells. In summary, PD-L1, HVEM, and B7H3 are expressed in osteosarcoma, with metastatic disease lesions expressing higher levels. We show for the first time that these ligands expressed on osteosarcoma cells positively correlate with each other and the presence of peritumoral T cell infiltration. Furthermore, osteosarcoma appears to be an intratumoral immune desert with significant resistance to effector T cells. Multiple agents targeting checkpoints are in clinical practice, and may have immune modulating benefit in osteosarcoma. |
| Databáze: | OpenAIRE |
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