Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer

Abstract

Obesity increases the risk of colorectal cancer (CRC) by 30%. The obese tumor microenvironment compromises antitumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang decoction (DFB) is a combined classical prescription from the “Synopsis of Prescriptions of the Golden Chamber”. We first determined that DFB regresses tumor growth in high‐fat diet–induced obese mice by expanding the TIM3− subset with intermediate expression of programmed cell death‐1 (PD‐1intTIM3−) and restricting the PD‐1hiTIM3+ subset. Transcription factor 1 (TCF1) is highly expressed in the PD‐1intTIM3− subset but is absent in PD‐1hiTIM3+ cells. We next confirmed that progenitor PD‐1intTCF+ cells robustly produce tumor necrosis factor‐α (TNFα) and interferon‐γ, whereas terminally differentiated PD‐1intTCF+ cells have defects in generating TNFα. With transgenic ob/ob mice, we found that DFB produces cooperative efficacy with anti‐PD‐1 (αPD‐1) by limiting the PD‐1hiTim3+ subset and amplifying the PD‐1intTCF+ population. Finally, we defined the recombinant chemokine C‐C‐motif receptor 2 (CCR2)+CD8+ subset as terminal Tex and identified that the differentiation from progenitor to terminal Tex is driven, at least in part, by the chemokine (C‐C motif) ligand 2 (CCL2)/CCR2 axis. The CCR2 inhibitor enhances the response to αPD‐1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in the obese microenvironment to restrain CRC progression. These findings provide unambiguous evidence that the traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and establish a strong rationale for further clinical verification.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma

“…Gegen Qinlian Decoction (GQD) was found to enhance anti-PD-1 monoclonal antibody therapy by modulating the gut microbiome and certain metabolic pathways, which in turn improved immune responses in colorectal cancer models [ 38 ]. Similarly, Dahuang Fuzi Baijiang Decoction (DFBD) showed efficacy in enhancing CD8 + T cell infiltration and reducing exhaustion markers like PD-1 in tumor microenvironments, although it did not exhibit a synergistic effect with ICIs [ 39 ]. Qingfei Jiedu Decoction (QFJDD) acted on lung cancer cells by downregulating PD-L1 expression and affecting key signaling pathways involved in the PD-1/PD-L1 axis [ 40 ].…”

Clinical characteristics and survival outcomes in patients aged 75 years or older with advanced colorectal cancer treated using traditional Chinese medicine: an observational retrospective study

“…TCM is an independent factor affecting PFS (11); when combined with chemotherapy and cetuximab or bevacizumab, TCM has been shown to prolong Frontiers in Pharmacology frontiersin.org liver by down-regulating the activation of cancer-associated fibroblasts mediated by CRC-derived ITGBL1-loaded extracellular vesicles (Li et al, 2022); thus, TCM has the unique characteristics of being multi-targeted and multi-linked, and may have a comprehensive therapeutic effect. TCM can also inhibit epithelial-mesenchymal transition by downregulating transforming growth factor-beta, thereby inhibiting invasion and metastasis of CRC cells (Ge et al, 2022), inhibit progression of CRC by suppressing CCL2 and preserving progenitor Tex in an obese microenvironment (Xu et al, 2022) and suppress growth and metastasis of 5-fluorouracil-sensitive/resistant CRC by inhibiting the Wnt singling pathway (Zhang et al, 2022).…”

Focus on T cell exhaustion: new advances in traditional Chinese medicine in infection and cancer

“…The recombinant chemokine C–C-motif receptor 2 (CCR2) + CD8 + subset was defined as Tex terminals and differentiation from progenitor cells to Tex terminals was driven, at least in part, by the chemokine (C–C motif) ligand 2 (CCL2)/CCR2 axis, CCR2 inhibitors enhanced the response to anti-PD-1 by promoting Tex progenitor cell counts. In conclusion, DFB inhibited CCL2 and retained progenitor Tex to suppress CRC progression in the obese microenvironment [ 131 ].…”