Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.

Molecular and immunological mechanisms of clonal evolution in multiple myeloma

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous subset of cells expanded during multiple pathological settings, including cancers. In tumors, MDSCs are dominant drivers of T-cell immunosuppression. To accomplish their job, they exploit multiple mechanisms ultimately leading to the paralysis of anti-tumor immunity. Among the variety of MDSC-ways of working within the tumor microenvironment, the generation of reactive species and the metabolic reprogramming have emerged as pivotal determinants of their immunosuppressive power. In this review we will overview integral mechanisms of MDSC-mediated immunosuppression in solid tumors, with a particular focus on Non-Hodgkin lymphoma.

MDSCs and T cells in solid tumors and non-Hodgkin lymphomas: an immunosuppressive speech.

CCL2 mediated IKZF1 expression promotes M2 polarization of glioma-associated macrophages through CD84-SHP2 pathway.

Multiple myeloma (MM) is an incurable plasma cell malignancy with the hallmark of immunodeficiency, including dysfunction of T cells, NK cells, and APCs. Dysfunctional APCs have been reported to play a key role in promoting MM progression. However, the molecular mechanisms remain elusive. Here, single‐cell transcriptome analysis of dendritic cells (DC) and monocytes from 10 MM patients and three healthy volunteers was performed. Both DCs and monocytes were divided into five distinct clusters, respectively. Among them, monocyte‐derived DCs (mono‐DC) were shown to develop from intermediate monocytes (IM) via trajectory analysis. Functional analysis showed that, compared with healthy controls, conventional DC2 (cDC2), mono‐DC, and IM of MM patients exhibited impaired antigen processing and presentation capacity. Moreover, reduced regulon activity of interferon regulatory factor 1 (IRF1) was found in cDC2, mono‐DC and IM of MM patients according to single‐cell regulatory network inference and clustering (SCENIC) analysis, while the downstream mechanisms were distinct. Specifically in MM patients, cathepsin S (CTSS) was markedly downregulated in cDC2, major histocompatibility complex (MHC) class II transactivator (CIITA) was significantly decreased in IM, in addition both CTSS and CIITA were downregulated in mono‐DC based on differentially expressed genes analysis. In vitro study validated that knockdown of Irf1 downregulated Ctss and Ciita respectively in mouse DC cell line DC2.4 and mouse monocyte/macrophage cell line RAW264.7, which ultimately inhibited proliferation of CD4+ T cells after being cocultured with DC2.4 or RAW264.7 cells. This current study unveils the distinct mechanisms of cDC2, IM, and mono‐DC function impairment in MM, offering new insight into the pathogenesis of immunodeficiency.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cas.15800

Distinct mechanisms of dysfunctional antigen‐presenting DCs and monocytes by single‐cell sequencing in multiple myeloma

Recent Insights into the Roles of PEST-Containing Nuclear Protein.

CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma.

A Novel Approach to Achieve Long-Lasting Antitumor Immunity in Multiple Myeloma

Dual blocking of CD47 and PD-L1 increases innate and adaptive immune responses in CTCL

OAB-001: Potentiating T cell activity against multiple myeloma through SUMOylation inhibition

Real-World Outcomes of CD19 CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Diffuse Large B-Cell Lymphoma

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