Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

Abstract

Multiple myeloma (MM) remains a lethal hematologic cancer characterized by the expansion of transformed plasma cells within the permissive bone marrow (BM) milieu. The emergence of relapsed and/or refractory MM (RRMM) is provoked through clonal evolution of malignant plasma cells that harbor genomic, metabolic and proteomic perturbations. For most patients, relapsed disease remains a major cause of overall mortality. Transforming growth factors (TGFs) have pleiotropic effects that regulate myelomagenesis as well as the emergence of drug resistance. Moreover, TGF-β modulates numerous cell types present with the tumor microenvironment, including many immune cell types. While numerous agents have been FDA-approved over the past 2 decades and significantly expanded the treatment options available for MM patients, the molecular mechanisms responsible for drug resistance remain elusive. Multiple myeloma is uniformly preceded by a premalignant state, monoclonal gammopathy of unknown significance, and both conditions are associated with progressive deregulation in host immunity characterized by reduced T cell, natural killer (NK) cell and antigen-presenting dendritic cell (DC) activity. TGF-β promotes myelomagenesis as well as intrinsic drug resistance by repressing anti-myeloma immunity to promote tolerance, drug resistance and disease progression. Hence, repression of TGF-β signaling is a prerequisite to enhance the efficacy of current and future immunotherapeutics. Novel strategies that incorporate T cells that have been modified to express chimeric antigen receptor (CARs), T cell receptors (TCRs) and bispecific T cell engagers (BiTEs) offer promise to block TGF-β signaling, overcome chemoresistance and enhance anti-myeloma immunity. Here, we describe the effects of TGF-β signaling on immune cell effectors in the bone marrow and emerging strategies to overcome TGF-β-mediated myeloma growth, drug resistance and survival.

Upregulated Expression of ERBB2/HER2 in Multiple Myeloma as a Predictor of Poor Survival Outcomes

“…We propose a model according to which the observed upregulation of ERB2/HER2 mRNA expression in MM cells is driven transcriptionally by several TFs ( Figure 2 C). The presented data expand our current knowledge regarding the networks of signaling pathways affecting the biology and clinical outcome of MM as well as emerging new molecular targets for chemotherapy-drug-resistant MM [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma

“… 29 , 31 Furthermore, TGFB plays a role here, which can create an immunosuppressive milieu and lead to drug resistance of modern immunotherapeutics. 32 In addition, our group has already shown that extrinsic TGF-β is capable of generating functional deficits in MSC. 19 In conclusion, our data lead to a broader understanding of the impact of the microenvironment on the progression of MGUS and SMM to MM, and MSCs are a potential therapeutic target.…”

Exosomal miRNAs in the Tumor Microenvironment of Multiple Myeloma

“…TGF-β is a strong regulator of normal B-cell development [ 88 ]. In MM, TGF-β is secreted at higher levels from both tumor and bone marrow stromal cells and promotes myelomagenesis, drug resistance, and osteoblast dysfunction [ 89 ]. In the hypoxic condition, in different cancers, it has been reported that TAMs release exosomal miR-223, which reshapes the TME and induces drug resistance by activating the PTEN/PI3K/AKT pathway [ 90 , 91 , 92 , 93 ].…”