Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy

Abstract

BackgroundCancer immunotherapy has generated significant excitement, mainly as a result of the development of immune checkpoint inhibitors. The blockade of PD-1 or its ligand with antibodies has resulted in impressive clinical efficacy. However, a subset of patients does not respond to biologic therapeutics, and another subset suffers from severe immune-related adverse events in certain cases. The modulation of the immune system with small molecules might yield surprising benefits.MethodsCD8+ cells were obtained through a magnetic cell sorting system (MACS), and their capabilities for IFN-γ release and PD-1 expression were analyzed. The in vitro effects of drugs were studied in a coculture system of tumor cells and activated CD8+ cells. We further isolated the primary tumor cells in tumor-bearing mice treated with CAI, DMF, 1-MT or a combination (CAI and DMF/CAI and 1-MT) and analyzed the percentages of CD8+ T cells and PD-1+CD8+ T cells among TILs. The selective anti-tumor immune reactions of the two drug combinations were confirmed in a coculture system consisting of B16-OVA cells and OVA-specific CTLs derived from OT-1 transgenic mice. The anti-tumor effects of the single drugs or combined therapies were assessed according to their capability to slow tumor growth and extend the life span of tumor-bearing mice, and they were compared with the effects of PD-1 antibody.ResultsCAI increased IFN-γ release from activated T cells, which might strengthen the anti-proliferative and anti-metastatic effects on cancer cells. However, CAI also stimulated IDO1-Kyn metabolic circuitry in the tumor microenvironment and facilitated tumor cell immune evasion. Combining CAI with 1-MT or DMF disrupted PD-1 expression and promoted IFN-γ production in CD8+ T cells, and it also increased T lymphocyte infiltration in the tumor microenvironment, inhibited tumor growth and prolonged the life spans of tumor-bearing mice.ConclusionInhibitors of the IDO1-Kyn-AhR pathway could abolish the negative effects of CAI on CD8+ T cells and result in complementary and beneficial anti-tumor immune effects. The combination of CAI with 1-MT or DMF greatly augmented the ability of CD8+ T cells to kill malignant cells and showed a strong anti-cancer capability that was superior to that of either of the single agents was is comparable with that of anti-PD-1 antibody. The combinations of small molecules utilized in this study may serve as valuable new immunotherapy strategies for cancer treatment.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0725-7) contains supplementary material, which is available to authorized users.

Blockade of IDO-kynurenine-AhR pathway promotes cell apoptosis in carboxyamidotriazole-induced tumor cell dormancy-apoptosis oscillation

“…In the early stage of tumorigenesis, CAI exerted a signi cant anti-cancer effect but in the stage of tumor relapse or progression, the role of CAI was relatively weakened, which can be observed in our animal experiments and previous clinical studies [20,21]. Recently we found that longterm CAI treatment produces a suppressive effect on CD8 + T cells through activation of IDO-Kyn-AhR cascade, which contributes to a weakened immune response in tumor initiation, growth and metastasis [22]. Providing evidence that the effects that hamper the in vivo anti-tumor capability of CAI might occur through the IDO-Kyn-AhR cascade.…”

Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases

“…This suggests that inhibition of Trp breakdown or KYNs/AhR signaling might be a promising therapeutic target in cancer to modulate the immunosuppressive tumor microenvironment. Jing et al have shown that combining carboxyamidotriazole (anti-cancer molecule) with IDO1-Kyn-AhR pathway inhibitors profoundly enhanced cancer immunotherapy in primary tumor cells isolated from tumor-bearing mice [ 124 ].…”

Selected 5-amino-1-aryl-1H-1,2,3-triazole scaffolds as promising antiproliferative agents

“…Chen et al (2017) reported that the combination of sorafenib and carboxyamidotriazole inhibited the proliferation of nonsmall cell lung cancer cells of A549 and NCI-H1975 lines in vitro, and Lewis lung carcinoma bearing mice [4]. The application of carboxyamidotriazole doi: https://doi.org/10.15407/ubj92.05.023 in the combination with 3′,4′-dimethoxyflavone or carboxyamidotriazole with 1-methyl-L-tryptophan resulted in higher anticancer activity than it was found for a single agent treatment [2].…”

“…1) capable of binding to and inhibiting of the non-voltage-operated Ca 2+ channels and blocking cellular Ca 2+ influx and release, cause a disruption of calcium channel-mediated signal transduction and inhibition of vascular endothelial growth factor signalling, endothelial proliferation, and angiogenesis [1]. This agent is also widely used in cancer therapy [2][3][4]. Carboxyamidotriazole inhibits growth of H345 small cell lung cancer cells via VEGF-dependent pathway.…”

“…2). Moreover, the amino-fused 1,2,3-triazole: 5-oxo-4,5,6,7,8,9-hexahydrobenzo [4,5]thieno [3,2-e] [1,2,3]triazolo [1,5-a]pyrimidine-3-carboxamide possessed a selective action towards melanoma SK-MEL-5 cells (GP = -31,50%) [8] (Fig. 2).…”