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

Priyanka S Rana; David C Soler; Jeries Kort; James J Driscoll

doi:10.3389/fcell.2022.1059715

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

Front Cell Dev Biol. 2022 Dec 12:10:1059715. doi: 10.3389/fcell.2022.1059715. eCollection 2022.

Authors

Priyanka S Rana^{1

2}, David C Soler³, Jeries Kort^{1

2

4}, James J Driscoll^{1

2

4}

Affiliations

¹ Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.
² Case Comprehensive Cancer Center, Cleveland, OH, United States.
³ The Brain Tumor and Neuro-Oncology Center, The Center of Excellence for Translational Neuro-Oncology, Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, United States.
⁴ Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.

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.

Keywords: CAR (chimeric antigen receptor) T-cells; T-cell; bispecific T-cell engager (BiTE) therapy; drug resistance; multiple myeloma; transforming growth factor-β.

Publication types

Review