cancers Review Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma Fatih M. Uckun 1,2,3 1 Norris Comprehensive Cancer Center and Childrens Center for Cancer and Blood Diseases, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA; [email protected] 2 Department of Developmental Therapeutics, Immunology, and Integrative Medicine, Drug Discovery Institute, Ares Pharmaceuticals, St. Paul, MN 55110, USA 3 Reven Pharmaceuticals, Translational Oncology Program, Golden, CO 80401, USA Simple Summary: This article provides a comprehensive review of new and emerging treatment strategies against multiple myeloma that employ precision medicines and/or drugs capable of improving the ability of the immune system to prevent or slow down the progression of multiple myeloma. These rationally designed new treatment methods have the potential to change the therapeutic landscape in multiple myeloma and improve the long-term survival outcome. Abstract: SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alter- natively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), Citation: Uckun, F.M. Overcoming the Immunosuppressive Tumor adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as Microenvironment in Multiple promising therapeutic platforms that can be employed in various combinations as part of a rationally Myeloma. Cancers 2021, 13, 2018. designed immunomodulatory strategy against an immunosuppressive tumor microenvironment https://doi.org/10.3390/ (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving cancers13092018 improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms. Academic Editor: David Wong Keywords: tumor microenvironment (TME); multiple myeloma (MM); immunomodulatory imide Received: 27 February 2021 drugs (IMiDs); autologous hematopoietic stem cell transplantation (ASCT); immune-checkpoint Accepted: 20 April 2021 receptors; spleen tyrosine kinase (SYK); transforming growth factor beta (TGF-β); bispecific T-cell Published: 22 April 2021 engagers (BiTEs); chimeric antigen receptor (CAR)-T Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The tumor microenvironment (TME) is one of the main contributors of a marked im- munobiological and clinical heterogeneity as well as clonal evolution in multiple myeloma (MM) [1–3]. Several cellular elements of the bone marrow (BM) microenvironment in MM patients contribute to the immune evasion, proliferation, and drug resistance of MM Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. cells [4–6], including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, + This article is an open access article “alternatively activated”, macrophages, CD38 regulatory B-cells (Bregs), and regulatory distributed under the terms and T-cells (Tregs) [4–6] (Figure1A). These immunosuppressive elements in bidirectional and conditions of the Creative Commons multi-directional crosstalk with each other inhibit both memory and cytotoxic effector Attribution (CC BY) license (https:// T-cell populations as well as natural killer (NK) cells [4–6]. MDSCs along with MM cell- creativecommons.org/licenses/by/ derived interleukin 10 (IL-10) [7–10], TGF-β, and IL-6 are also known to impair dendritic 4.0/). cell (DC) maturation and their antigen-presenting function, which further accentuates Cancers 2021, 13, 2018. https://doi.org/10.3390/cancers13092018 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 15 Cancers 2021, 13, 2018 2 of 14 with MM cell‐derived interleukin 10 (IL‐10) [7–10], TGF‐, and IL‐6 are also known to impair dendritic cell (DC) maturation and their antigen‐presenting function, which fur‐ thether immunosuppression accentuates the immunosuppression [6]. In addition to [6]. their In addition immune-suppressive to their immune activity‐suppressive mediated ac‐ bytivity their mediated secretion by of their IL-10 secretion (an activator of IL‐10 of Tregs(an activator and M2 of macrophages), Tregs and M2 and macrophages), TGF-β (an inhibitorand TGF‐ of (an both inhibitor cytotoxic of T-cellsboth cytotoxic and NK T cells),‐cells and M2 macrophagesNK cells), M2 alsomacrophages promote MMalso pro cell‐ proliferation,mote MM cell angiogenesis, proliferation, and angiogenesis, chemotherapy and resistance chemotherapy [11–13 ]resistance (Figure1A). [11–13] Nonclinical (Figure studies1A). Nonclinical in animal studies models in of animal MM have models demonstrated of MM have that demonstrated exosomes serve that asexosomes regulators serve of theas regulators signaling networksof the signaling within networks the BM microenvironment, within the BM microenvironment, activate anti-apoptotic activate mech- anti‐ anismsapoptotic promoted mechanisms by oncogenic promoted proteins by oncogenic such asproteins the signal such transducer as the signal and transducer activator and of transcriptionactivator of transcription 3 (STAT3), and 3 (STAT3), cause immunosuppression and cause immunosuppression by facilitating theby growthfacilitating of MD- the SCsgrowth [14– of19 ].MDSCs Exosome-activated [14–19]. Exosome MDSCs‐activated have beenMDSCs implicated have been in implicated development in develop of other‐ immunosuppressivement of other immunosuppressive cells, such as Tregs, cells, tumor-promoting such as Tregs, tumor angiogenesis,‐promoting proliferation angiogenesis, of MMproliferation cells, and of increased MM cells, osteoclast and increased activity osteoclast contributing activity to thecontributing lytic bone to lesions the lytic [14 –bone19]. Complementinglesions [14–19]. theComplementing immunosuppressive the immunosuppressive TME, T-cell exhaustion TME, combined T‐cell exhaustion with high-level com‐ expressionbined with ofhigh immune-checkpoint‐level expression of ligands immune on‐checkpoint MM cells ligands are the mainon MM contributors cells are the to main the immunecontributors evasion to the of immune MM cells evasion [20–23]. of MM cells [20–23]. Figure 1. ImmunosuppressiveFigure TME 1. inImmunosuppressive MM. (A) MM cells TMEsecrete in several MM. (A cytokines) MM cells including secrete several IL‐6, TGF cytokines‐ (TGF), including and IL‐ IL-6, 10 [7–10] that inhibit DCs, CTLs,TGF-β but(TGF), stimulate and IL-10 Tregs. [7– 10MDSCs] that inhibit are stimulated DCs, CTLs, by butM2 stimulatemacrophages Tregs. via MDSCs IL‐6 and are stimulate stimulated by M2 macrophages as well asM2 Tregs macrophages via IL‐10. MDSC via IL-6 inhibit and stimulate CTLs and M2 NK macrophages cells via IL‐ as10. well See astext Tregs for detailed via IL-10. discussion. MDSC inhibit CTLs and NK cells via IL-10. See text for detailed discussion. (B) Lactate shuttle in TME. Lactate derived from MM cells stimulates Tregs and M2 macrophages, but it inhibits TILs, CTL, NK cells, and γδT cells. See text for detailed discussion. Cancers 2021, 13, 2018 3 of 14 2. Immunomodulatory Imide Drugs (IMiDs) to Overcome the Immunosuppressive TME in MM IMiDs augment the activity of cereblon E3 ubiquitin ligase complex and enhance the effector functions as well as the proliferative expansion of cytotoxic T-cells and NK cells through cereblon-dependent proteolytic degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), increased production of IL-2 and IFN-γ with concomitant reduction in IL-10 production and suppression of Tregs [24–27]. They also block the pro- inflammatory cytokines TNF-α and IL-6, thereby decreasing the contributions of MDSC and M2 macrophages to the immunosuppressive milieu of the TME. Notably, in a IMiD- conditioned TME, T-cell activation is facilitated, as it no longer requires co-stimulation by antigen-presenting DCs [24–27]. In addition, IMiDs trigger caspase-mediated apoptosis in MM cells and impair their interaction with the protective BM stroma [28]. Efforts are under- way to further enhance the clinical potency of IMiDs by combining them with modulators of cereblon E3-ligase, such as iberdomide, that accelerate IMiD-mediated degradation of IKZF1/IKZF3 [26,27]. Due to the considerable added benefit of the IMiD thalidomide, a combination of bortezomib, thalidomide, and dexamethasone (VTD) has become a stan- dard induction regimen [29]. New generation IMiDs, including lenalidomide (Revlimid; Celgene) and pomalidomide (Pomalyst; Celgene) have potent immune modulatory effects and have significantly improved the survival outcomes of newly diagnosed as well as R/R MM patients [30]. IMiDs are used in combination with Proteasome inhibitors (PIs), such as bortezomib, carfilzomib, or ixazomib, in standard of care for MM to achieve optimal anti-tumor activity as well as inhibit angiogenesis within the TME [30]. Recent studies in- dicated that PIs also