Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow Transplant 2011 Aug;17(8):1133-45
Date
05/04/2011Pubmed ID
21536144DOI
10.1016/j.bbmt.2011.03.011Scopus ID
2-s2.0-79960218752 (requires institutional sign-in at Scopus site) 137 CitationsAbstract
Multiple myeloma is an incurable plasma cell malignancy. Patients who fail conventional therapy are frequently treated with hematopoietic stem cell transplantation (HSCT), which results in reduced tumor burden, but the patients subsequently relapse from sites of chemotherapy-resistant disease. Using the 5T33 murine model of myeloma and a previously successful immunotherapy regimen consisting of autologous (syngeneic) HSCT and cell-based vaccine administration, we were unable to improve survival of myeloma-bearing mice. The 5T33 tumor line, similar to malignant plasma cells from myeloma patients, expresses high levels of programmed death receptor ligand-1 (PD-L1), which binds to the inhibitory receptor, PD-1. We observed that T cells from myeloma-bearing mice express high levels of PD-1, which has also been observed in patients with multiple myeloma. These PD-1(+) T cells were exhausted and produced IL-10. Based on these observations, we combined HSCT with whole-cell vaccination and PD-L1 blockade. Inhibition of the PD-1/PD-L1 pathway with HSCT and whole-cell vaccination increased the survival of myeloma-bearing mice from 0% to 40%. These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease.
Author List
Hallett WH, Jing W, Drobyski WR, Johnson BDAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinBryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Apoptosis
B7-H1 Antigen
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Disease Models, Animal
Female
Hematopoietic Stem Cell Transplantation
Hepatitis A Virus Cellular Receptor 2
Humans
Immunologic Memory
Immunosuppressive Agents
Killer Cells, Natural
Male
Mice
Mice, Inbred C57BL
Multiple Myeloma
Plasma Cells
Receptors, Virus
