TY - JOUR
T1 - Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade
AU - Hallett, William H.D.
AU - Jing, Weiqing
AU - Drobyski, William R.
AU - Johnson, Bryon D.
N1 - Funding Information:
Financial disclosure: This research was supported by the Midwest Athletes Against Childhood Cancer Fund , Milwaukee, WI, NIH Grant HL064603 , and by a fellowship grant from the Medical College of Wisconsin Cancer Center . The authors acknowledge Megan Whitaker and Laura McOlash for outstanding technical support, Kristen Barr for experimental assistance, Dr. Jeff Woodliff in the MCW Flow Cytometry Core for cell separations, Dr. Calvin William for use of flow cytometric equipment, and Dr. Jill Gershan and Dr. Bruce Blazar for helpful discussions. The authors also thank NIH HL064603, the MCW Cancer Center, and the Midwest Athletes Against Childhood Cancer for financial support.
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Myeloma
KW - PD-L1
KW - Transplantation
KW - Tumor Vaccine
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U2 - 10.1016/j.bbmt.2011.03.011
DO - 10.1016/j.bbmt.2011.03.011
M3 - Article
C2 - 21536144
AN - SCOPUS:79960218752
SN - 1083-8791
VL - 17
SP - 1133
EP - 1145
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 8
ER -
