Co-evolution of Immune Response in Multiple Myeloma: Implications for Immune Prevention

Abstract

Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to MM or progress over many years. Therefore, MGUS provides a unique opportunity to surveil changes in the BM tumor microenvironment throughout disease progression. It is increasingly appreciated that MGUS cells carry many of the genetic changes found in MM. Prior studies have also shown that MGUS cells can be recognized by the immune system, leading to early changes in the BM immune environment compared to that of healthy individuals, including alterations in both innate and adaptive immunity. Progression to clinical MM is associated with attrition of T cells with stem memory-like features and instead accumulation of T cells with more terminally differentiated features. Recent clinical studies have suggested that early application of immune-modulatory drugs, which are known to activate both innate and adaptive immunity, can delay the progression to clinical MM. Understanding the biology of how the immune response and tumors coevolve over time is needed to develop novel immune-based approaches to achieve durable and effective prevention of clinical malignancy.

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

“…However, we also found overexpression of inhibitory molecules such as LAG-3, TIGIT and IDO1, which may affect the anti-myeloma immune response in SMM. Patients with SMM showed a wide heterogeneity in their immune compartment ( 22 ), which let us to identify 4 clusters based on their gene expression profiles. Importantly, patients in cluster 2 had higher expression of cytotoxic molecules (GZMB, PRF, GNLY, IFNG) but also upregulation of some inhibitory molecules (LAG3, KLRC1, CD96, BTLA), suggesting the presence of exhausted T cells.…”

Single-cell transcriptional analysis of the immune tumour microenvironment during myeloma disease evolution

“…Immune dysregulation plays a role in controlling disease progression in cancer [23], including myeloma [24][25][26]. However, it is only with the rapid uptake of single cell profiling that we are now beginning to unravel the diverse landscape of cell types, their molecular states, and dynamic interactions associated with disease processes in myeloma [14,[27][28][29][30]. Challenges towards these efforts remain, including extreme inter-patient variability and a paucity of samples from patients with early precursor disease.…”

Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche

“…The exact role of osteoclast in the BM milieu is not fully elucidated. However, the impact in terms of bone involvement prompted a plethora of preclinical and clinical studies aiming to target bone remodeling and, indirectly, tumor progression ( 29 , 36 , 37 ). All targets mentioned above could be potentially valuable in the next-generation immunotherapy for MM patients.…”

“…The observation that immune activation and exhaustion appear early in the pathogenesis of the preneoplastic phase termed monoclonal gammopathy of undetermined significance (MGUS) ( 44 ) suggests that features of the immune response necessary for the long-term stability and persistence of immunity, such as stem-like memory T cells, are critical determinants of immune control. Specific immune response targets may also be relevant, as it may be more effective to therapeutically target clonal rather than subclonal mutations or critical clone features such as stemness ( 36 ). Although the spatial elements of the immune response in hematologic malignancies have hardly been investigated, pathologists and radiologists have long recognized that myeloma is multifocal in its growth (hence the name multiple myeloma).…”