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.
Department of Surgical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
Thorac Cancer. 2021 Oct;12(19):2564-2573. doi: 10.1111/1759-7714.14137. Epub 2021 Sep 6.
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).
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.
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).
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.
Src 同源区 2 结构域含磷酸酶 2（SHP2）是一种新型的 Kirsten 大鼠肉瘤癌基因（KRAS）突变型癌症的靶点。我们回顾性研究了 SHP2 在接受免疫治疗的 KRAS 突变型非小细胞肺癌（NSCLC）中的意义及其与肿瘤微环境（TME）的关系。
入组 61 例接受免疫治疗的晚期 KRAS 突变型 NSCLC 患者。采用下一代测序（NGS）对突变状态进行分析。通过免疫组织化学（IHC）分析 SHP2、磷酸化 SHP2（pSHP2）和程序性死亡配体 1（PD-L1）的表达。采用定量多重免疫荧光细胞化学（mIFC）分析来描述 TME。
32 例肿瘤细胞和免疫细胞中的 SHP2 呈异质性表达，25 例（78.1%）样本中高表达（H 评分>10）。SHP2 和 pSHP2 的表达水平呈正相关。与 PD-L1<50%相比，PD-L1≥50%的肿瘤中基质 SHP2（s-SHP2）更高（p=0.039）。通过定量 mIFC 分析，基质中 s-SHP2 的表达与 CD8、CD4、CD68 和 PD-L1 水平呈正相关。SHP2 高表达患者完全缓解（PR）和疾病稳定（SD）的比例分别为 100.0%和 80.0%，而进展（PD）的比例为 50.0%。SHP2 高表达与无进展生存期（PFS）和总生存期（OS）延长相关（p<0.001，p=0.013）。SHP2 和 PD-L1 高表达的患者 PFS 更长（p<0.001）。
SHP2 高表达可预测晚期 KRAS 突变型 NSCLC 免疫治疗的疗效和生存获益。SHP2 可能在肿瘤细胞和免疫细胞中均有作用，值得进一步研究 SHP2 抑制在 TME 中的潜在不同作用。
