Abstract
Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma (MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses.
Highlights
Multiple myeloma (MM) is a malignant plasma cell disease mainly located in the bone marrow (BM) in multiple ‘niches’
Our study demonstrated that endothelial cells (ECs) can act as semi-professional antigen presenting cells (APCs) stimulating a regulatory tumor-specific CD8+ T cell population with suppressive function within BM of MM patients [11]
A very recent single-cell RNA sequencing study revealed that mature CD14+ monocytes/macrophages lose human leukocyte antigen (HLA) class II surface expression as early as in the monoclonal gammopathy of undetermined significance (MGUS) phase resulting in T cell suppression [76]
Summary
Multiple myeloma (MM) is a malignant plasma cell disease mainly located in the bone marrow (BM) in multiple ‘niches’ These provide a microenvironment that promotes tumor survival and progression. Tumor plasma cells have the ability to promote a tolerant microenvironment and the activation of immunosuppressive mechanisms to counteract effective immune responses These include impairment of antigen processing and presentation, and T cell response, NK and NKT cell dysfunctions, local recruitment, expansion and activation of immune suppressor cells like T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs), and differentiation of the protumoral tumor-associated macrophages and Th17 cells [9,10,11] (Figure 1). We describe interactions between BM tumor plasma cells and different immune cells and provide an overview of the current knowledge on immunotherapeutic strategies
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