2. Academic Validation
  3. FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity

FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity

  • Nat Commun. 2024 May 30;15(1):4590. doi: 10.1038/s41467-024-48397-9.
Enni Chen # 1,  Jiawei Wu # 1,  Jiajia Huang # 1,  Wancui Zhu 1,  Haohui Sun 1,  Xiaonan Wang 1,  Dagui Lin 1,  Xiaodi Li 1,  Dingbo Shi 1,  Zhiqiao Liu 1,  Jinsheng Huang 1,  Miao Chen 2,  Fangyun Xie 3,  Wuguo Deng 4 5
Affiliations

Affiliations

  • 1 Sun 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.
  • 2 Sun 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. chenmiao@sysucc.org.cn.
  • 3 Sun 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. xiefy@sysucc.org.cn.
  • 4 Sun 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. dengwg@sysucc.org.cn.
  • 5 Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Guangdong, China. dengwg@sysucc.org.cn.
  • # Contributed equally.
PMID: 38816360 DOI: 10.1038/s41467-024-48397-9
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.

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