Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

Abstract

Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

Prediction of IDO1 Inhibitors by a Fingerprint‐Based Stacking Ensemble Model Named IDO1Stack

“…Then we stratified the data according to an 8 : 2 ratio into a training set and a test set. Moreover, the external validation set included 222 compounds collected from multiple literature [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in 2021-2023 in order to evaluate the generalization performance of the model. The number of IDO1 inhibitors and noninhibitors in each data set was listed in Table 1.…”

“…In this work, inhibitor data were collected from the PubChem database [33] and several literature in 2021-2023, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] essentially covering the currently known IDO1 inhibitors. For compounds collected from the PubChem database, we first removed compounds with no activity values or no literature support, and ensured that the remaining compounds were assigned one of the following activity value types: IC 50 , EC 50 , K d , K i .…”

Mechanism and strategies of immunotherapy resistance in colorectal cancer

“…In addition, kynurenine is negatively correlated with CD8+ T cell infiltration in the CRC TME. The induction of FOXP3 and Treg polarization by kynurenine may contribute to this process ( 96 , 97 ).…”

In-situ formed thermosensitive hydrogel amplifies statin-mediated immune checkpoint blockade for coordinated tumor chemo-immunotherapy

“…The tumor killing effect of ICB therapy heavily depends on the abundance of CTLs in tumor tissues ( HaanenConverting, 2017 ; Frederico et al, 2021 ; Zhang et al, 2022 ). Low tumor infiltration of CTLs is the main reason for the low response rate of ICIs ( Balermpas et al, 2014 ; Stanton and Disis, 2016 ; Paijens et al, 2021 ).…”