Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy
Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li
Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li
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Research Article Oncology

Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy

Abstract

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti–programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

Authors

Daqiang Song, Yushen Wu, Jie Li, Jiazhou Liu, Ziying Yi, Xiaoyu Wang, Jiazheng Sun, Liuying Li, Qianxue Wu, Yuru Chen, Huiying Fang, Tiankuo Luan, Huimin Du, Jing Huang, Weiyan Peng, Yuxian Wei, Fan Li, Qin Li, Li Zhang, Yong Zhu, Jingyuan Wan, Guosheng Ren, Hongzhong Li

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Figure 5

Deficiency of IGF2 significantly reduces the expression levels of CXCL12 and PD-L1 through the inactivation of Akt signaling in CAFs.

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Deficiency of IGF2 significantly reduces the expression levels of CXCL12...
(A) KEGG analysis of scRNA-Seq data showing the enriched signaling pathways in the fibroblasts from EO771 tumors of WT mice in comparison with those of Igf2-cKO mice (n = 3 mice per group). P adjust, adjusted P value. (B) KEGG analysis of RNA-Seq showing the enriched signaling pathways in WT CAFs compared with Igf2–/– CAFs. NES, normalized enrichment score. (C) Activation of the Akt pathway in WT or Igf2–/– CAFs treated with linsitinib (5 μM) or mouse rIGF2 protein (10 μM) was detected by Western blotting. (D and E) Expression levels of CXCL12 (D) and PD-L1 (E) on WT or Igf2–/– CAFs treated with MK2206 (10 μM) or SC79 (10 μM) were determined by flow cytometry (n = 3). (F and G) Expression levels of CXCL12 (F) and PD-L1 (G) on the negative control (shNC) or shIGF1R human CAFs were determined by flow cytometry (n = 3). (H) Migration changes of CD8+ T cells cocultured with shNC or shIGF1R human CAFs (n = 3). (I) The percentage of IFN-γ+ CD8+ T cells cocultured with shNC or shIGF1R human CAFs was determined by flow cytometry (n = 3). Data are presented as the mean ± SEM (D–I). P values were determined by hypergeometric test (A) and 1-way ANOVA (D–I).