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 6

IGF2 blockade synergistically enhances the therapeutic efficacy of ICB.

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IGF2 blockade synergistically enhances the therapeutic efficacy of ICB. ...
(A) IGF2 expression in the indicated cell clusters based on scRNA-Seq analysis of melanoma data (GSE115978) from the GEO database. (B) IGF2 expression in pretreatment tumors from patients with melanoma who had different treatment responses to anti–PD-1 (GSE115978). TPM, transcripts per million. (C) OS of patients with melanoma who received anti–PD-1 treatment (GSE115978) based on IGF2 expression in pretreatment tumors. (D–G) Tumor growth (D), mouse survival (E), percentage of CD8+ T cells (F), and percentage of IFN-γ+ or TNF-α+ CD8+ T cells (G) in EO771 tumors from WT or Igf2-cKO mice treated with anti-IgG or anti–PD-1 (10 mg/kg) (n = 5 mice per group). (H–J) Tumor growth and mouse survival (H), serum CXCL12 levels and expression of PD-L1 on CAFs (I), and percentage of CD8+ T cell abundance and IFN-γ+ and TNF-α+ CD8+ T cells (J) in MC38 tumor–bearing WT mice after treated with linsitinib (10 mg/kg), anti–CTLA-4 (5 mg/kg), or their combination in WT mice (n = 5 mice per group). (K) Growth of MC38 tumors in WT or iDTRfl/fl S100a4CreERT mice treated with vehicle or linsitinib (10 mg/kg) (n = 5 mice per group). Data are presented as the mean ± SEM (B, F, G, and H–J). P values were determined by 2-tailed, unpaired Student’s t test (I), 1-way ANOVA (B, F, G, and J), 2-way ANOVA (A, D, H, and K), or log-rank test (C, E, and H). Veh., vehicle.