EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ
Wei-Tao Zhuang, Lan-Lan Pang, Li-Yang Hu, Jun Liao, Jian-Hua Zhan, Ting Li, Ri-Xin Chen, Jia-Ni Zheng, An-Lin Li, Wen-Yan Yu, Tian-Qin Mao, Liang Chen, Yu-Jian Huang, Shao-Dong Hong, Jing Li, Jun-Han Wu, Yi-Ming Zeng, Meng-Juan Yang, Hai-Qing Zeng, Ya-Xiong Zhang, Li Zhang, Wen-Feng Fang
Wei-Tao Zhuang, Lan-Lan Pang, Li-Yang Hu, Jun Liao, Jian-Hua Zhan, Ting Li, Ri-Xin Chen, Jia-Ni Zheng, An-Lin Li, Wen-Yan Yu, Tian-Qin Mao, Liang Chen, Yu-Jian Huang, Shao-Dong Hong, Jing Li, Jun-Han Wu, Yi-Ming Zeng, Meng-Juan Yang, Hai-Qing Zeng, Ya-Xiong Zhang, Li Zhang, Wen-Feng Fang
View: Text | PDF
Research Article Immunology Oncology

EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ

Abstract

Epidermal growth factor receptor–activating (EGFR-activating) mutations are established biomarkers of resistance to immune checkpoint blockade (ICB) in lung cancer, yet the precise molecular mechanism and effective therapeutic strategies remain elusive. In this study, we show that EGFR overexpression and amplification recapitulated the negative effect of EGFR driver mutations on the ICB response, indicating a proactive involvement of EGFR signaling in antagonizing the antitumor immune response. Functional studies unveiled that EGFR activation suppressed the cellular response to IFN-γ following ICB treatment across multiple cancer models. This impairment in IFN-γ responsiveness further limited the upregulation of T cell–recruiting chemokines and antigen presentation, resulting in reduced T cell infiltration and activation, ultimately undermining antitumor immunity. Mechanistically, EGFR promotes Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) activation to accelerate STAT1 dephosphorylation, leading to premature termination of the IFN-γ response. SHP2 inhibition restored ICB sensitivity in EGFR-activated tumors, significantly reducing tumor burden while maintaining a favorable safety profile. Our findings suggest that the EGFR/SHP2 axis functions as a molecular brake to disrupt the initiation and amplification of the IFN-γ–mediated antitumor response during immunotherapy. This discovery unveils a potential avenue to overcome immunotherapy resistance in EGFR-driven tumors, particularly lung cancer, through SHP2-targeted combination strategies.

Authors

Wei-Tao Zhuang, Lan-Lan Pang, Li-Yang Hu, Jun Liao, Jian-Hua Zhan, Ting Li, Ri-Xin Chen, Jia-Ni Zheng, An-Lin Li, Wen-Yan Yu, Tian-Qin Mao, Liang Chen, Yu-Jian Huang, Shao-Dong Hong, Jing Li, Jun-Han Wu, Yi-Ming Zeng, Meng-Juan Yang, Hai-Qing Zeng, Ya-Xiong Zhang, Li Zhang, Wen-Feng Fang

×

Figure 9

Combining ICB with SHP2 inhibition is effective and potentially safe to overcome primary resistance to immunotherapy in EGFR-mutated lung cancer.

Options: View larger image (or click on image) Download as PowerPoint
Combining ICB with SHP2 inhibition is effective and potentially safe to ...
(A) EGFR19del/T790M-transgenic C57BL/6 mice were treated with doxycycline for 6 weeks to induce lung cancer, and then with IgG or anti–PD-1 antibody (200 μg, 2 times/week i.p.), SHP099 (75 mg/kg daily p.o.), or anti–PD-1 combined with SHP099 for 2 weeks. Representative H&E staining of lungs from each treatment group (n = 4–5 mice/group). Scale bars: 500 μm (enlarged insets, bottom). Original magnification, ×100. (B) Number of lung tumor nodules (left) and total tumor burden (right) at treatment endpoint. (C) Body weight change of transgenic mice during treatment. (D) H&E staining of primary organ tissues from transgenic mice after completion of the indicated treatment. (E) Pathologic grade of organ-specific inflammation. Scale bars: 200 μm (lung, heart, and liver) and 100 μm (colon, bottom row). (F) Schematic illustration of how EGFR activation desensitizes tumors to ICB treatment through SHP2-mediated abrogation of the cellular IFN-γ response, which compromises chemokine production and antigen presentation. Inhibition of SHP2 augments the tumor-intrinsic IFN-γ response, resulting in increased CTL recruitment and activation, which facilitates the reinforcement of a positive feedback loop and resensitizes EGFR-activated tumors to ICB treatment. The schematic in F was drawn using BioRender.com. Data are presented as the mean ± SD (B) and mean ± SEM (C). *P < 0.05 and **P < 0.01, by 1-way ANOVA with Tukey’s test.