FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity
Enni Chen1, Jiawei Wu1, Jiajia Huang1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Abstract:
Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Insights
FLI1 in nasopharyngeal carcinoma (NPC) impairs anti-tumor immunity by boosting kynurenine (Kyn) production. Inhibiting FLI1 restores immune responses and enhances tumor eradication, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Nasopharyngeal carcinoma (NPC) often exhibits an immunosuppressive tumor microenvironment (TME), leading to immunotherapy failure.
- Tumor-intrinsic factors play a significant role in mediating this immunosuppression and hindering anti-tumor immunity.
Purpose of the Study:
- To identify key molecular mediators of immunosuppression in NPC.
- To elucidate the mechanism by which FLI1 contributes to immune evasion in NPC.
- To evaluate the therapeutic potential of targeting the FLI1 pathway.
Main Methods:
- Investigated the role of FLI1 in NPC-mediated immunosuppression.
- Utilized mechanistic studies to understand the regulatory cascade involving FLI1, CBP, STAT1, and IDO1.
- Assessed the impact of FLI1 inhibition on T cell function and tumor eradication in vivo.
Main Results:
- Identified tumor-intrinsic FLI1 as a critical factor impairing T cell anti-tumor immunity.
- Demonstrated that FLI1 upregulates IDO1 expression via the CBP/STAT1 pathway in response to IFN-γ, increasing kynurenine (Kyn) production.
- Showed that FLI1 inhibition reverses immunosuppression, enhances anti-tumor immune responses, and promotes tumor eradication.
Conclusions:
- FLI1-mediated kynurenine metabolism is a key immune evasion mechanism in nasopharyngeal carcinoma.
- Pharmacological inhibition of FLI1 represents a promising therapeutic strategy for overcoming immunotherapy resistance in NPC.
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