Modified Shenlingbaizhu decoction suppresses colon cancer via enhancing memory-like Tfh differentiation and B cell responses.

[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.