.png){kind=icon}
.png){kind=icon}
Return
Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective
.png){kind=icon}
OA
AI
DOI：10.3389/fimmu.2026.1769281.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
IntroductionMultiple myeloma (MM) develops within a profoundly immunosuppressive bone marrow (BM) microenvironment. CD38; a multifunctional ectoenzyme highly expressed on malignant plasma cells; contributes to this niche by degrading nicotinamide adenine dinucleotide (NAD+) into ADPR; which fuels adenosine (ADO) production through CD38/CD203a/CD73 enzymatic pathway. CD38_targeting monoclonal antibodies (mAbs); including daratumumab (DARA) and isatuximab (ISA); exert antitumor activity through direct cytotoxicity and immune modulation; however; resistance to these agents remains a major clinical challenge. Understanding how CD38 enzymatic activity and adenosinergic metabolism evolve during therapy is essential for improving treatment efficacy.MethodsThis study investigates (i) the enzymatic functions of CD38; (ii) the in vitro effects of DARA and ISA on CD38_mediated NAD+ degradation in primary MM cells and a representative MM cell line; and (iii) the in vivo dynamics of ADO and its metabolite inosine (INO) in BM and peripheral blood (PB) plasma from MM patients receiving DARA monotherapy.ResultsIn vitro; both DARA and ISA promoted NAD⁺ degradation with accumulation of ADPR. In vivo; ADO concentrations in BM plasma remained consistently in the micromolar range and declined only modestly during treatment; whereas INO progressively increased; leading to a gradual attenuation of the BM -PB gradient. These findings indicate that adenosinergic metabolism remains active during DARA therapy; likely sustained by reduced CD38 expression due to antibody_driven internalization or microvesicle (MV) release; together with adenosine deaminase (ADA) -mediated ADO degradation.DiscussionDespite CD38_targeted therapy; ADO concentrations in the BM remain well above the activation thresholds of P1 purinergic receptors; suggesting persistent adenosinergic immunosuppression. This sustained ADO production may contribute to a tolerogenic BM niche that promotes immune evasion and therapeutic resistance. These results support the rationale for combining CD38_directed antibodies with agents targeting adenosinergic signaling to enhance antitumor immunity and improve clinical outcomes in MM.
Keywords:
immunosuppression
multiple myeloma
daratumumab
isatuximab
immunotherapy
CD38
adenosine
inosine
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.
Journal
IF:
5.9
Papers:
4.9W
Citations:
22.7W
Organization
View more organizations