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- Title
Identification and validation of ecto-5' nucleotidase as an immunotherapeutic target in multiple myeloma.
- Authors
Ray, Arghya; Song, Yan; Du, Ting; Buon, Leutz; Tai, Yu-Tzu; Chauhan, Dharminder; Anderson, Kenneth C.
- Abstract
Interaction of plasmacytoid dendritic cells (pDCs) with multiple myeloma (MM) cells, T- or NK-effector cells in the bone marrow (BM) microenvironment induces tumor cell growth, as well as inhibits innate and adaptive immune responses. Defining pDC-MM interaction-triggered immunosuppressive mechanism(s) will enable design of interventional therapies to augment anti-MM immunity. In the present study, we show that pDC-MM interactions induce metabolic enzyme Ecto-5' Nucleotidase/CD73 in both pDCs and MM cells. Gene expression database from MM patients showed that CD73 levels inversely correlate with overall survival. Using our pDC-MM coculture models, we found that blockade of CD73 with anti-CD73 Abs: decreases adenosine levels; activates MM patient pDCs; triggers cytotoxic T lymphocytes (CTL) activity against autologous patient MM cells. Combination of anti-CD73 Abs and an immune-stimulating agent TLR-7 agonist enhances autologous MM-specific CD8+ CTL activity. Taken together, our preclinical data suggest that the therapeutic targeting of CD73, alone or in combination with TLR-7 agonist, represents a promising novel strategy to restore host anti-MM immunity.
- Subjects
MULTIPLE myeloma; CYTOTOXIC T cells; BONE marrow cells; MELPHALAN; BORTEZOMIB; CELL growth; DENDRITIC cells
- Publication
Blood Cancer Journal, 2022, Vol 12, Issue 4, p1
- ISSN
2044-5385
- Publication type
Article
- DOI
10.1038/s41408-022-00635-3