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The JAK-STAT pathway regulates CD38 on myeloma cells in the bone marrow microenvironment: therapeutic implications
Daisuke Ogiya1,2, Jiye Liu1, Hiroto Ohguchi3
1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Abstract:
Anti-CD38 monoclonal antibody (MoAb) treatments including daratumumab (DARA) are effective therapies for both newly diagnosed and relapsed multiple myeloma (MM). In this study, we examined the soluble factors that modulate CD38 expression and are associated with sensitivity to DARA-mediated antibody-dependent cellular cytotoxicity (ADCC) in the bone marrow (BM) microenvironment. Importantly, primary BM stromal cell (BMSC) culture supernatant (BMSC-sup) and interleukin-6 (IL-6) downregulated CD38 expression and reduced DARA-mediated ADCC. Both cytokine profiling of the BMSC-sup and genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout screening in MM cell lines identified and validated the JAK-STAT3 signaling pathway mediating CD38 downregulation, whereas the JAK-STAT1 pathway mediated CD38 upregulation. STAT3 knockdown abrogated BMSC-sup- and IL-6-induced CD38 downregulation on MM cell lines. We also confirmed that STAT3 and CD38 is negatively correlated in primary MM cells. To assess potential clinical relevance, pharmacological inhibition of the JAK-STAT pathway on BMSC-sup-induced CD38 downregulation was further examined. JAK inhibitor ruxolitinib inhibited STAT3 phosphorylation in MM cell lines, upregulated CD38 expression in MM cell lines and primary patient MM cells, and augmented DARA-mediated ADCC against MM cell lines. Taken together, our results suggest that CD38 expression on MM cells in the BM microenvironment is regulated by both STAT1 (positively) and STAT3 (negatively), and that inhibition of the JAK-STAT3 pathway represents a novel therapeutic option to enhance CD38 expression and anti-CD38 MoAb-mediated MM cytotoxicity.
Insights
Soluble factors in the bone marrow microenvironment regulate CD38 expression in multiple myeloma (MM). Inhibiting the JAK-STAT3 pathway enhances CD38 expression and anti-CD38 antibody-dependent cellular cytotoxicity (ADCC) for improved MM treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Anti-CD38 monoclonal antibodies (MoAbs) like daratumumab (DARA) are effective multiple myeloma (MM) therapies.
- CD38 expression levels influence the efficacy of DARA-mediated antibody-dependent cellular cytotoxicity (ADCC).
- The bone marrow (BM) microenvironment contains soluble factors that can modulate CD38 expression and MM cell sensitivity to therapy.
Purpose of the Study:
- To investigate soluble factors within the BM microenvironment that affect CD38 expression on MM cells.
- To identify signaling pathways regulating CD38 expression in MM.
- To explore the therapeutic potential of modulating these pathways to enhance DARA efficacy.
Main Methods:
- Primary bone marrow stromal cell (BMSC) culture supernatant and recombinant interleukin-6 (IL-6) were used to treat MM cell lines.
- Cytokine profiling and genome-scale CRISPR-Cas9 knockout screening were employed to identify signaling pathways.
- STAT3 knockdown and pharmacological JAK-STAT pathway inhibition (ruxolitinib) were used to assess pathway roles.
- CD38 expression and DARA-mediated ADCC were measured in MM cell lines and primary patient cells.
Main Results:
- BMSC supernatant and IL-6 downregulated CD38 expression and reduced DARA-mediated ADCC.
- The JAK-STAT3 pathway was identified as mediating CD38 downregulation, while JAK-STAT1 mediated upregulation.
- STAT3 knockdown blocked IL-6-induced CD38 downregulation, and STAT3 was negatively correlated with CD38 in primary MM cells.
- JAK inhibitor ruxolitinib upregulated CD38 expression and enhanced DARA-mediated ADCC in MM cell lines and primary patient cells.
Conclusions:
- CD38 expression in the MM BM microenvironment is dynamically regulated by STAT1 (upregulation) and STAT3 (downregulation).
- Inhibition of the JAK-STAT3 pathway is a promising strategy to increase CD38 expression on MM cells.
- Enhancing CD38 expression via JAK-STAT3 inhibition can augment the efficacy of anti-CD38 MoAb therapies like daratumumab against multiple myeloma.
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