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Updated: Aug 12, 2025
Author Spotlight: Exploring Strategies for Successful Immune Response Against Tumors
Published on: August 16, 2024
Dynamic single-cell RNA-seq analysis reveals distinct tumor program associated with microenvironmental remodeling and
Mengping Chen1, Yike Wan1, Xin Li1
1Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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.
Insights
Single-cell analysis reveals that decreased immune reactivity in multiple myeloma (MM) tumors predicts poor response to VCD therapy. This immune suppression is linked to tumor cell signaling and an immunosuppressive microenvironment, impacting patient survival.
Area of Science:
- Hematology
- Cancer Biology
- Immunology
Background:
- Multiple myeloma (MM) is a plasma cell malignancy with poorly understood drug sensitivity mechanisms.
- Identifying molecular drivers of treatment response and patient outcomes in MM is crucial.
Purpose of the Study:
- To investigate tumor and immune cell reprogramming in MM patients undergoing VCD therapy using single-cell RNA sequencing.
- To identify molecular programs associated with drug sensitivity and clinical outcomes in MM.
Main Methods:
- Single-cell RNA sequencing of tumor cells and immune cells from 10 MM patients before and after VCD treatment.
- Analysis of gene expression patterns, including immune-related programs and microenvironment interactions.
- Correlation of molecular findings with drug response and patient survival.
Main Results:
- VCD treatment altered tumor cell programs, decreasing unfolded protein response and metabolic pathways while increasing stress and immune reactivity.
- Low expression of tumor cell immune-reactive programs correlated with poor VCD response and survival, linked to impaired antigen presentation and immune escape.
- A connection was found between tumor immune reactivity and an immunosuppressive microenvironment, characterized by exhausted T cells, NK cells, and monocytes.
- YBX1 expression was associated with reduced immune signaling and infiltration, predicting a poor prognosis.
Conclusions:
- Single-cell analysis provides a detailed view of tumor and immune reprogramming in MM during targeted therapy.
- A specific tumor program integrating tumoral signaling and immune microenvironment changes was identified.
- These findings offer insights into the mechanisms of drug sensitivity and resistance in multiple myeloma.
