The JAK-STAT pathway regulates CD38 on myeloma cells in the bone marrow microenvironment: therapeutic implications

Abstract

<jats:p>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 which 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 CRISPR-Cas9 knockout screening in MM cell lines identified and validated JAK-STAT3 signaling pathway mediating CD38 downregulation, whereas 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 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 JAK-STAT3 pathway represents a novel therapeutic option to enhance CD38 expression and anti-CD38 MoAb-mediated MM cytotoxicity.</jats:p>

Ruxolitinib reverses checkpoint inhibition by reducing programmed cell death ligand‐1 (PD‐L1) expression and increases anti‐tumour effects of T cells in multiple myeloma

“…The RUX inhibition of both STAT3 and STAT1 results in a variety of potential anti‐MM effects, as well as other benefits of this JAK inhibitor. First, selective STAT3 inhibition leads to more effective upregulation of CD38 expression on MM cells, thus suggesting that the combination treatment of CD38‐targeting immunotherapy together with RUX, the JAK pathway inhibitor, may help enhance sensitivity to daratumumab‐mediated antibody‐dependent cytotoxicity, thus providing the rationale for this combination to be used to treat patients with MM 36 . Second, more recent data suggests that RUX may be able to mitigate the hyperinflammatory state observed in patients experiencing coronavirus disease 2019 (COVID‐19)‐associated cytokine storm 37 .…”

Signaling Pathway Mediating Myeloma Cell Growth and Survival

“…These results suggest that daratumumab-induced ADCC may be attenuated in the BM microenvironment. Conversely, a JAK inhibitor ruxolitinib blocks STAT3 phosphorylation and upregulates CD38 expression, thereby augmenting daratumumab-induced ADCC against MM cell lines in vitro [ 70 ].…”

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

“…Anti CD38 MoAbs have several anti-myeloma and microenvironment activities, such as complement-dependent cytotoxicity (CDC), ADCC, direct myeloma killing, enhancement of the immune system, inhibition of CAM-DR, and enhancement of bone remodeling as above. CD38 expression is independent of the maturation of MM cells’ cytogenetic abnormality [ 153 , 176 ], but is dependent on serum IL-6 level, which increases in disease progression [ 177 ]. Anti-CD38 MoAbs contribute to the enhancement of the immune system [ 178 ].…”