High SHP2 expression determines the efficacy of PD‐1/PD‐L1 inhibitors in advanced KRAS mutant non‐small cell lung cancer

Thoracic Cancer

Zhou Zhang¹  Shao‐Kun Chuai¹  Fang‐Ping Xu²  Hong‐Ling Liang³  Dong‐Kun Zhang⁴  Heng‐Hui Zhang⁵  Qing Zhou⁶  Yu Chen⁶  Xue‐Ning Yang⁶  Yi‐Long Wu⁶  Wen‐Qing Yan⁶  Zhi‐Yi Lv⁶  Dan‐Xia Lu⁶  Zhi Xie⁶  Yu‐Min Zhong⁶  Jie Jiang⁶  Wei‐Bang Guo⁶  Jin‐Ji Yang⁶  Xu‐Chao Zhang⁶  Hui‐Bo Feng⁶ 

[1]Burning Rock Biotech Shanghai China

[2]Department of Pathology and Laboratory Medicine Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences Guangzhou China

[3]Department of Surgical Oncology Affiliated Cancer Hospital and Institute of Guangzhou Medical University Guangzhou China

[4]Department of Thoracic Surgery Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences Guangzhou China

[5]Genecast Biotechnology Wuxi China

[6]Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou China

关键词: immunotherapy;    KRAS;    non‐small cell lung cancer;    SHP2;   

DOI  :  10.1111/1759-7714.14137

来源: DOAJ

【 摘 要 】

Abstract Background Src homology region 2 domain‐containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non‐small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME). Methods Sixty‐one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next‐generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho‐SHP2 (pSHP2), and programmed death ligand 1 (PD‐L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME. Results SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H‐score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s‐SHP2) was higher in tumors with PD‐L1 ≥50% versus PD‐L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s‐SHP2 had positive correlation with CD8, CD4, CD68, and PD‐L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression‐free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD‐L1 had longer PFS (p < 0.001). Conclusion High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.

【 授权许可】

Unknown