Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions

Danielle M. Lussier, Lauren O'Neill, Lizbeth M. Nieves, Megan S. McAfee, Susan A. Holechek, Andrea W. Collins, Paul Dickman, Jeffrey Jacobsen, Pooja Hingorani, Joseph Blattman

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcomareactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)96-106
Number of pages11
JournalJournal of Immunotherapy
Volume38
Issue number3
DOIs
StatePublished - Mar 27 2015

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Osteosarcoma
Immunity
Cytotoxic T-Lymphocytes
T-Lymphocytes
Antibodies
Bone Neoplasms
Tumor Burden
Tumor Cell Line
Disease Progression
Neoplasms
Neoplasm Metastasis
Ligands
Drug Therapy
Survival
Therapeutics

Keywords

  • antibody therapy
  • metastatic osteosarcoma
  • osteosarcoma
  • PD-L1
  • Programmed death receptor-1

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. / Lussier, Danielle M.; O'Neill, Lauren; Nieves, Lizbeth M.; McAfee, Megan S.; Holechek, Susan A.; Collins, Andrea W.; Dickman, Paul; Jacobsen, Jeffrey; Hingorani, Pooja; Blattman, Joseph.

In: Journal of Immunotherapy, Vol. 38, No. 3, 27.03.2015, p. 96-106.

Research output: Contribution to journalArticle

Lussier, DM, O'Neill, L, Nieves, LM, McAfee, MS, Holechek, SA, Collins, AW, Dickman, P, Jacobsen, J, Hingorani, P & Blattman, J 2015, 'Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions', Journal of Immunotherapy, vol. 38, no. 3, pp. 96-106. https://doi.org/10.1097/CJI.0000000000000065
Lussier, Danielle M. ; O'Neill, Lauren ; Nieves, Lizbeth M. ; McAfee, Megan S. ; Holechek, Susan A. ; Collins, Andrea W. ; Dickman, Paul ; Jacobsen, Jeffrey ; Hingorani, Pooja ; Blattman, Joseph. / Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. In: Journal of Immunotherapy. 2015 ; Vol. 38, No. 3. pp. 96-106.
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