Dynamic single-cell RNA-seq analysis reveals distinct tumor program associated with microenvironmental remodeling and drug sensitivity in multiple myeloma

Abstract

Background Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of malignant plasma cells. Despite extensive research, molecular mechanisms in MM that drive drug sensitivity and clinic outcome remain elusive. Results Single-cell RNA sequencing was applied to study tumor heterogeneity and molecular dynamics in 10 MM individuals before and after 2 cycles of bortezomib–cyclophosphamide–dexamethasone (VCD) treatment, with 3 healthy volunteers as controls. We identified that unfolded protein response and metabolic-related program were decreased, whereas stress-associated and immune reactive programs were increased after 2 cycles of VCD treatment. Interestingly, low expression of the immune reactive program by tumor cells was associated with unfavorable drug response and poor survival in MM, which probably due to downregulation of MHC class I mediated antigen presentation and immune surveillance, and upregulation of markers related to immune escape. Furthermore, combined with immune cells profiling, we uncovered a link between tumor intrinsic immune reactive program and immunosuppressive phenotype in microenvironment, evidenced by exhausted states and expression of checkpoint molecules and suppressive genes in T cells, NK cells and monocytes. Notably, expression of YBX1 was associated with downregulation of immune activation signaling in myeloma and reduced immune cells infiltration, thereby contributed to poor prognosis. Conclusions We dissected the tumor and immune reprogramming in MM during targeted therapy at the single-cell resolution, and identified a tumor program that integrated tumoral signaling and changes in immune microenvironment, which provided insights into understanding drug sensitivity in MM.

C-reactive protein impairs immune response of CD8+T cells via FcγRIIb-p38MAPK-ROS axis in multiple myeloma

“…The ssGSEA analysis of the MMRF CoMMpass cohort showed lower infiltration of activated CD4 + and CD8 + T cells in patients with MM with high serum CRP ( figure 1C ). Furthermore, in our single-cell sequencing data, 20 21 elevated serum CRP in patients with MM correlated with lower cytotoxicity score and higher inhibitory score in CD8 + T cells ( figure 1D ). Analysis of clustering was shown in online supplemental figure S1A,B .…”

CXCL7 plays a crucial role in facilitating extramedullary invasion and osteolytic damage in multiple myeloma

“…However, myeloma presents a distinct scenario in which the altered biological behavior of neoplastic cells results in multi-organ dysfunction. Genomic variations contribute to the unique biological characteristics exhibited by these plasma cells [17]. The high degree of intratumor heterogeneity in multiple myeloma results in distinct biological characteristics among different tumor cell subsets, posing challenges for effective treatment and leading to diverse target organ damage and clinical manifestations in patients [18,19].…”

Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma

“…Low immune-reactive gene expression indicated poor survival and non-responsiveness to drugs, likely by reduced MHC-class I-mediated antigen presentation capacity (APC) and immune surveillance, and upregulation of immune escape genes. The authors also found a connection between the tumor-intrinsic immune reactive program and the immunosuppressive microenvironment arising from immune cell exhaustion and checkpoint molecule expression in T-cells, NK cells, and monocytes [284]. Another study focusing specifically on SCTS of DCs and monocytes from 10 MM patients found five distinct clusters for each cell type [286].…”