Abstract
The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.
Overview
- The study investigates the role of itaconate, a Krebs cycle byproduct, in tumor cells. It shows that increased itaconate production promotes tumor immunogenicity and anti-tumor immune responses. The study identifies thimerosal, a vaccine preservative, as a specific inducer of itaconate production in tumor cells. The study also explores the mechanism behind itaconate production and its impact on antigen presentation-related gene expression. The primary objective of the study is to understand the role of itaconate in tumor cells and identify potential therapeutic targets for immunotherapy. The study uses mouse lymphoma model to test the efficacy of itaconate induction by thimerosal in promoting tumor immunogenicity and anti-tumor immune responses.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions. It shows that increased itaconate production promotes tumor immunogenicity and anti-tumor immune responses. The study identifies thimerosal as a specific inducer of itaconate production in tumor cells. The study also explores the mechanism behind itaconate production and its impact on antigen presentation-related gene expression. The key findings of the study are that itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. The study also shows that IRG1 deficiency markedly impaired tumor response to thimerosal treatment.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study identifies a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provides a translational means to increase immunotherapy efficacy. The study also identifies thimerosal as a specific inducer of itaconate production in tumor cells, which could be used as a therapeutic target for immunotherapy. The study suggests that future research should explore the use of itaconate induction by thimerosal in combination with other immunotherapies to enhance their efficacy. The study also suggests that future research should explore the use of itaconate induction by thimerosal in other cancer models to validate its role in promoting tumor immunogenicity and anti-tumor immune responses.