Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions.
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 osteosarcoma-reactive 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.
*Molecular and Cellular Biology Graduate Program †Center for Infectious Diseases and Vaccinology §Molecular Biosciences and Biotechnology ‡Postbaccalaureate Research Education Program, School of Life Sciences, Arizona State University, Tempe ∥Center for Cancer and Blood Disorders ¶Department of Pathology and Laboratory Medicine, Phoenix Children's Hospital #Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
Danielle M
DM
Lussier
Lauren
L
O'Neill
Lizbeth M
LM
Nieves
Megan S
MS
McAfee
Susan A
SA
Holechek
Andrea W
AW
Collins
Paul
P
Dickman
Jeffrey
J
Jacobsen
Pooja
P
Hingorani
Joseph N
JN
Blattman
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor