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Published on: October 13, 2023
Modified Shenlingbaizhu decoction suppresses colon cancer via enhancing memory-like Tfh differentiation and B cell
Gurong Jiang1, Xinyi Yan1, Yeyun Zheng1
1The Key Laboratory of Molecular Biology, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Background:
The late-stage clinical trial of immune checkpoint inhibitor (ICI) shows poor response in microsatellite stable (MSS) colorectal cancer patients. Developing effective therapeutic strategies to enhance and prolong antitumor activity remains a significant challenge for tumor types characterized by poor T-cell infiltration.
Purpose:
This study aims to explore if Modified Shenlingbaizhu Decoction (MSD) regulates anti-tumor immune response in the tumor microenvironment (TME).
Methods:
The components of MSD extracts were characterized by high performance liquid chromatography (HPLC) analysis. Single-cell RNA sequencing (scRNA-seq), flow cytometry analysis and immunofluorescence were adopted to resolve the immune landscape in MSS mice model. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of serum IgG.
Results:
MSD promoted antitumor immunity by increasing memory-like follicular helper T cells (Tfh) and B cells in mouse colon adenocarcinoma (COAD) tumors, rather than through CD8+ T cells or myeloid cells. Analysis of scRNA-seq results suggested MSD enhanced the secretion of CCL20 and CXCL13. Neutralizaion of CCL20 impaired the effects of MSD in promoting the migration of high endothelial venules (HEV)-associated B cells into tumor nests and facilitating the formation of tumor-associated aggregates (TAAs). Depletion of B cells reduced the generation of memory-like Tfh cells and impaired their stemness, thereby attenuated the therapeutic efficacy of MSD in COAD-bearing mice. During secondary immune responses, memory-like Tfh cells could rapidly transition to an effector state, promoting B cell differentiation into plasma cells and enhancing IgG antibody secretion. Mechanically, MSD upregulated Jarid2 expression in Tfh cells. Knockdown of Jarid2 in Tfh cells led to a decrease in the number of memory-like Tfh cells with stemness, and reduced the expression of the key receptor ICOS that interacted with B cells.
Conclusions:
Mutual interaction between B cells and memory-like Tfh cells was promising immune response for the treatment of MSS COAD. MSD promoted the formation of TAA to intensify Tfh cell/B cell collaboration in a CCL20 dependent-manner.
Insights
Modified Shenlingbaizhu Decoction (MSD) enhances antitumor immunity in microsatellite stable colorectal cancer by boosting Tfh and B cell collaboration. This immune response, mediated by CCL20, promotes B cell aggregation and antibody secretion, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC).
- Developing strategies to overcome poor T-cell infiltration and enhance antitumor immunity in MSS CRC is crucial.
Purpose of the Study:
- To investigate the immunomodulatory effects of Modified Shenlingbaizhu Decoction (MSD) in the tumor microenvironment (TME) of MSS colorectal cancer.
- To determine if MSD can enhance anti-tumor immune responses in a preclinical model.
Main Methods:
- Characterization of MSD components using High-Performance Liquid Chromatography (HPLC).
- Analysis of the immune landscape in an MSS mouse model using single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunofluorescence.
- Quantification of serum IgG levels via Enzyme-Linked Immunosorbent Assay (ELISA).
Main Results:
- MSD increased memory-like follicular helper T (Tfh) cells and B cells, enhancing antitumor immunity in mouse colon adenocarcinoma (COAD) models.
- MSD upregulated CCL20 and CXCL13, with CCL20 crucial for B cell migration and tumor-associated aggregate (TAA) formation.
- B cell depletion or CCL20 neutralization impaired MSD's therapeutic effects, highlighting the Tfh cell-B cell axis.
- MSD upregulated Jarid2 in Tfh cells, promoting Tfh stemness and interaction with B cells via ICOS.
Conclusions:
- The interaction between B cells and memory-like Tfh cells represents a promising immune response for MSS COAD treatment.
- MSD promotes TAA formation, enhancing Tfh cell/B cell collaboration in a CCL20-dependent manner.
- MSD offers a potential therapeutic approach by modulating the TME to improve antitumor immunity in MSS CRC.
