Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression

Abstract

Immunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.

Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level

“…CD4 T cells play a critical role in developing and sustaining effective antitumor immunity and are crucial in orchestrating the immune response through activation and maintenance of cytotoxic CD8 T cells, secretion of Eff cytokines, and direct cytotoxicity against tumor cells. 35 Recent studies in MM have shown that CD4 T cells elicit effective anti-MM responses 36,37 and that decreased CD4 T-cell counts are associated with adverse prognosis and diminished treatment responses, 28,38,39 highlighting an important functional role of CD4 T cells.…”

Significance of a tumor microenvironment-mediated P65-miR-30a-5p-BCL2L11 amplification loop in multiple myeloma

“…Studies have showed dynamic interaction of myeloma cells with the surrounding tumor microenvironment in a mutually pro-survival fashion [15][16][17] . The tumor microenvironmental network promotes myeloma cell growth, survival, proliferation, drug resistance and angiogenesis by affecting various epigenetic and genetic molecular events, including miRNA alterations.…”

Immunophenotypic Characteristics of Bone Marrow Microenvironment Cellular Composition at the Biochemical Progression of Multiple Myeloma

“…The relapse status we referred not to healthy donors but to the MRD-negative status, which, from our point of view, is closest to the actual condition of the BM microenvironment of patients after effective treatment and which is modulated in the disease-progression process. In turn, more heavily pretreated patients have highly proliferative malignant clones that downregulate pathways required for tumor immunosurveillance [40], which limits the reliability of relating our data to healthy individuals.…”