Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade

William H.D. Hallett; Weiqing Jing; William R. Drobyski; Bryon D. Johnson

doi:10.1016/j.bbmt.2011.03.011

Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade

William H.D. Hallett, Weiqing Jing, William R. Drobyski, Bryon D. Johnson^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

143 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1133-1145
Number of pages	13
Journal	Biology of Blood and Marrow Transplantation
Volume	17
Issue number	8
DOIs	https://doi.org/10.1016/j.bbmt.2011.03.011
State	Published - Aug 2011

Funding

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.

Keywords

Immunotherapy
Myeloma
PD-L1
Transplantation
Tumor Vaccine

ASJC Scopus subject areas

Transplantation
Hematology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbmt.2011.03.011

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@article{3eef8b063c5f4ef69c25f8941ba2764c,

title = "Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade",

abstract = "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.",

keywords = "Immunotherapy, Myeloma, PD-L1, Transplantation, Tumor Vaccine",

author = "Hallett, \{William H.D.\} and Weiqing Jing and Drobyski, \{William R.\} and Johnson, \{Bryon D.\}",

note = "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.",

year = "2011",

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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.

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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.

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Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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