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 4

IGF2 facilitates the interaction between CAFs and T cells through CXCL12 and PD-L1 signaling.

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IGF2 facilitates the interaction between CAFs and T cells through CXCL12...
(A) Heatmap showing the transcripts of differentially expressed genes in WT and Igf2–/– CAFs (n = 5). (B) Volcano plot showing the expression of differentially expressed genes and violin plot representing the expression of Cxcl12 and Cd274 in a fibroblast cluster from EO771 tumors from WT or Igf2-cKO mice (n = 3 mice per group). (C) Expression changes of Cxcl12 and CD274 in the fibroblast subpopulations from EO771 tumors based on pseudotime analysis. (D) Network presenting CXCL signaling among cell clusters in EO771 tumors from WT or Igf2-cKO mice (n = 3 mice per group). The line thickness denotes the strength of the interactions. (E) stRNA-Seq analysis showing the CXCL signaling among cell clusters in the IGF2hi or IGF2lo COAD tissues. The line thickness denotes the strength of the interactions. SMC, smooth muscle cell. (F) Ligand-receptor interaction of CXCL12 with its receptors CXCR4 and ACKR3 in the indicated cell clusters in EO771 tumors from WT or Igf2-cKO mice (n = 3 mice per group). Commun., communication; Prob., probability; max, maximum; min, minimum. (G) Levels of serum CXCL12 in EO771 or MC38 tumor–bearing WT or Igf2-cKO mice were determined by ELISA (n = 5 mice per group). (H) PD-L1 expression on CAFs from EO771 or MC38 tumors was detected by flow cytometry (n = 5 mice per group). (I and J) Expression of CXCL12 (I) and PD-L1 (J) in the WT or Igf2–/– CAFs with or without linsitinib treatment (5 μM) or murine rIGF2 protein (10 μM) was detected by flow cytometry (n = 3). (K) Migration ratio of T cells cocultured with WT or Igf2–/– CAFs treated with anti-IgG or anti-CXCL12 neutralizing antibody (2 ng/mL). (L) Percentage of IFN-γ+ or TNF-α+ CD8+ T cells cocultured with WT or Igf2–/– CAFs treated with anti-IgG or anti–PD-L1 neutralizing antibody (0.2 μg/mL). Data are presented as the mean ± SEM (B and G–L). P values were determined by 2-tailed, unpaired Student’s t test (B, G and H), 1-way ANOVA (I and J), or 2-way ANOVA (K and L).