Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

Area of Science:

• Immunology
• Oncology
• Bone Biology

Background:

• Multiple myeloma (MM) cells enhance osteoclast (OC) activity, causing bone lesions.
• The role of OCs in creating a suppressive immune microenvironment in the bone marrow (BM) of MM patients is not fully understood.

Purpose of the Study:

• To investigate how OCs influence the immune microenvironment in multiple myeloma.
• To identify immune checkpoint molecules and T-cell regulators expressed by OCs that contribute to immune suppression.

Main Methods:

• Analysis of immune checkpoint molecule and T-cell metabolism regulator expression during osteoclastogenesis.
• Assessment of OC-mediated protection of myeloma cells against T-cell cytotoxicity.
• Evaluation of the effects of targeting molecules like PD-L1, IDO, and CD38 on T-cell responses.

Main Results:

• OCs protect myeloma cells by inhibiting CD4+ and CD8+ T-cell proliferation.
• Upregulated immune checkpoint molecules (PD-L1, Galectin-9, HVEM, CD200) and T-cell metabolism regulators (IDO, CD38) were found on OCs.
• Galectin-9 induced T-cell apoptosis, and APRIL secreted by OCs increased PD-L1 expression on myeloma cells.
• Targeting PD-L1, IDO, or CD38 partially or fully restored T-cell anti-myeloma activity.

Conclusions:

• Osteoclasts play a critical role in establishing a suppressive immune microenvironment in the multiple myeloma bone marrow.
• Targeting immune checkpoint molecules and cytokines expressed by OCs represents a promising strategy to enhance anti-myeloma immunity.