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

Obesity contributes to about 30% incidence of colorectal cancer (CRC). Obese tumor microenvironment compromises anti-tumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang Decoction (DFB), a combined classical prescription from “Synopsis of Golden Chamber”, modulates the differentiation of tumor-infiltrating CD8+ T cells, we firstly demonstrate that DFB regresses tumor growth in high-fat diet induced obese mice via expanding PD-1intTIM3- and restricting PD-1hiTIM3+ subset. TCF1 is highly expressed in PD-1intTIM3- subset but is absent in PD-1hiTIM3+ cells. We next confirm that progenitor PD-1intTCF+ cells robustly produce TNFɑ and IFNγ while terminally differentiated PD-1intTCF+ cells have defects in generating TNFɑ. With transgenic ob/ob mice, we find that DFB produces cooperative efficacy with anti-PD-1 (ɑPD-1) by limiting PD-1hiTim3+ subset and amplifying PD-1intTCF+ population. Finally, we define CCR2+CD8+ subset as teminal Tex and identify that the differentiation from progenitor to terminal Tex is driven, at least in part, by CCL2/CCR2 axis. CCR2 inhibitor enhances the response to ɑPD-1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in obese microenvironment to restrain CRC progression. These finds provide unambiguous evidence that traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and give rise to strong rationale for further clinical verification.