Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy.
• Increased arginase activity suppresses T-cell immune responses in cancer.
• The role of arginase 1 (ARG1) in MM pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of ARG1 in a mouse model of MM.
• To evaluate the therapeutic potential of arginase inhibition in MM.

Main Methods:

• Utilized the Vκ*MYC mouse model for multiple myeloma.
• Assessed ARG1 expression in myeloid cells and its correlation with tumor progression.
• Measured L-arginine levels and T-cell proliferation in MM-bearing mice.
• Investigated the effects of pharmacological arginase inhibition and myeloid-specific ARG1 deletion on tumor progression.
• Examined the impact of arginase inhibition on bortezomib efficacy and cardiotoxicity.

Main Results:

• ARG1 expression in myeloid cells correlated with MM progression and decreased L-arginine levels.
• T-cell proliferation was suppressed in MM-bearing mice, but restored by arginase inhibition.
• Myeloid-specific ARG1 deletion and pharmacological inhibition significantly delayed tumor progression.
• Arginase inhibition did not enhance bortezomib's anti-myeloma effects but completely prevented bortezomib-induced cardiotoxicity.

Conclusions:

• Arginase 1 plays a significant role in suppressing anti-myeloma immunity.
• Arginase inhibitors show potential as an adjunct therapy for MM, particularly for mitigating adverse cardiac events associated with proteasome inhibitors like bortezomib.