Abstract
Simple SummaryA common characteristic of multiple myeloma (MM) is the dysfunction of patients’ immune system, a condition termed immunosuppression. This state is mainly due to alterations in the number and functionality of the principal immune populations. In this setting, immunotherapy has acquired high relevance in the last years and the investigation of agents that boost the immune system represent a field of interest. In the present review, we will summarize the main cellular and molecular alterations observed in MM patients’ immune system. Furthermore, we will describe the mechanisms of action of the four immunotherapeutic drugs approved so far for the treatment of MM, which are part of the group of monoclonal antibodies (mAbs). Finally, the immune-stimulating effects of several therapeutic agents are described due to their potential role in reversing immunosuppression and, therefore, in favoring the efficacy of immunotherapy drugs, such as mAbs, as part of future pharmacological combinations.Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.
Highlights
Multiple myeloma (MM), the second most common hematological malignancy, is characterized by the accumulation of malignant plasma cells in the bone marrow (BM) leading to hypercalcemia, bone destruction, anemia and renal failure [1]
Belantamab mafodotin exerts its antimyeloma effect through four known mechanisms: (i) antibody dependent cellular cytotoxicity (ADCC) mediated by NK cells; (ii) recruitment of macrophages to promote antibody dependent cellular phagocytosis (ADCP); (iii) disruption of microtubules and subsequent G2/M cell-cycle arrest followed by apoptosis after the release of the monomethyl auristatin F (MMAF) toxin in the cytoplasm of myeloma cells [147] and (iv) induction of immunogenic cell death (ICD) [148], which is a mechanism characterized by the ability of dying cells to elicit robust adaptive immune responses against altered self-antigens or cancer-derived neo-epitopes [154]
With respect to PD-L1 expression in MM cells, panobinostat, entinostat and ricolinostat (HDAC6 inhibitor) upregulated PD-L1 in these cells probably by histone acetylation of the PDL1 gene promoter [163]. In line with these results, reanalyzing gene expression microarray data generated in our lab [192], we have found an increase in PD-L1 mRNA expression after treatment of MM.1S cells with panobinostat
Summary
Multiple myeloma (MM), the second most common hematological malignancy, is characterized by the accumulation of malignant plasma cells in the bone marrow (BM) leading to hypercalcemia, bone destruction, anemia and renal failure [1]. An impaired response against viral antigens in MM patients has been observed [17], which may be associated to the increased expression of suppressor of cytokine signaling 1 (SOCS1) by T CD8+ subset, which, in turn, inhibits IL-2, IL-6 and IFN-γ production in these same cells, attenuating Th1 and cytotoxic T lymphocytes (CTL)-mediated responses [18]. High serum soluble PD-L1 levels are associated with poor prognosis in MM patients [37,38] and PD-L1+ MM cells show greater drug resistance [39] and higher levels of antiapoptotic proteins [31] Considering all these data, three main mAbs targeting PD-1 (nivolumab, pembrolizumab and pidilizumab) have been evaluated in MM. The definite niche of checkpoint inhibitors in the treatment of MM patients will be based on the results of clinical trials testing their optimal partners and times of administration
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