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Potent anti-myeloma efficacy of dendritic cell therapy in combination with pomalidomide and programmed death-ligand 1 blockade in a preclinical model of multiple myeloma

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Abstract

Dendritic cell (DC)-based vaccines are recognized as a promising immunotherapeutic strategy against cancer; however, the efficacy of immunotherapy with DCs is controlled via immune checkpoints, such as programmed death-ligand 1 (PD-L1). PD-L1 expressed on DC and tumor cells binds to programmed death-1 (PD-1) receptors on the activated T cells, which leads to the inhibition of cytotoxic T cells. Blocking of PD-L1 on DC may lead to improve the efficacy of DC therapy for cancer. Here we demonstrated that DC vaccination in combination with pomalidomide and programmed death-ligand 1 (PD-L1) blockade inhibited tumor growth of a multiple myeloma (MM) mouse model. DCs + pomalidomide with dexamethasone + PD-L1 blockade significantly inhibited immune immunosuppressive factors and promoted proportions of immune effector cells in the spleen and tumor microenvironment. Additionally, functional activities of cytotoxic T lymphocytes and NK cells in spleen were enhanced by DCs + pomalidomide with dexamethasone + PD-L1 blockade. Taken together, this study identifies a potential new therapeutic approach for the treatment of MM. These results also provide a foundation for the future development of immunotherapeutic modalities to inhibit tumor growth and restore immune function in MM.

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Data availability

The data that support the findings of this study are openly available in 17th International Myeloma Workshop September 2019 at https://doi.org/10.1016/j.clml.2019.09.272 [51], and the 62nd American Society of Hematology Annual Meeting & Exposition 2019 at https://doi.org/10.1182/blood-2019-127964 [52].

Abbreviations

BM:

Bone marrow

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

CTLs:

Cytotoxic T lymphocytes

DC:

Dendritic cell

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethylsulfoxide

ELISA:

Enzyme-linked immunosorbent

ELISPOT:

Interferon (IFN)-γ enzyme-linked immunospot

FBS:

Fetal bovine serum

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

imDC:

Immature DC

IMiDs:

Immunomodulatory drugs

MM:

Multiple myeloma

MOPC:

Mineral-oil-induced plasmacytomas

MHC:

Major histocompatibility

MDSCs:

Myeloid-derived suppressor cells

mAbs:

Monoclonal antibodies

NK:

Natural killer

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

PC:

Plasma cell

PBS:

Phosphate-buffered saline

PIs:

Proteasome inhibitors

PS:

Penicillin/streptomycin

rm:

Recombinant murine

rmIL:

Recombinant mouse interleukin

TNF-α:

Tumor necrosis factor-alpha

Th1:

T helper type 1

Tregs:

Regulatory T cells

TGF-β:

Transforming growth factor-beta

VEGF:

Vascular endothelial growth factor

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Acknowledgements

Je-jung Lee has received honoraria for speaking at the 17th international myeloma workshop september 2019 [51], and the 62nd American Society of Hematology Annual Meeting and Exposition 2019 [52].

Funding

This research was supported by grants (2018R1A5A2024181, NRF-2018R1C1B5041536, NRF-2020R1A2C2010098) from the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (MEST), Republic of Korea.

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Author notes

  1. Tan-Huy Chu and Manh-Cuong Vo contributed equally to this work.

Authors and Affiliations

  1. Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea

    Tan-Huy Chu, Manh-Cuong Vo, Hye-Seong Park, Thangaraj Jaya Lakshmi, Sung-Hoon Jung & Je-Jung Lee

  2. Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea

    Manh-Cuong Vo, Sung-Hoon Jung, Hyeoung-Joon Kim & Je-Jung Lee

  3. Vaxcell-Bio Therapeutics, Hwasun, Jeollanamdo, Republic of Korea

    Je-Jung Lee

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  1. Tan-Huy Chu
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Contributions

MCV, THC, SHJ, and JJL designed the study. MCV, THC, HSP, and TJL performed the research and analyzed the data. MCV and JJL wrote the article. JJL, SHJ, and HJK contributed intellectually to the research.

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Correspondence to Sung-Hoon Jung or Je-Jung Lee.

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Chu, TH., Vo, MC., Park, HS. et al. Potent anti-myeloma efficacy of dendritic cell therapy in combination with pomalidomide and programmed death-ligand 1 blockade in a preclinical model of multiple myeloma. Cancer Immunol Immunother 70, 31–45 (2021). https://doi.org/10.1007/s00262-020-02654-0

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