| Objective: Non-small cell lung cancer(NSCLC)is the leading cause of cancer-related death in China.Kirsten rat sarcoma viral oncogene(KRAS)is one of the most common proto-oncogenes in NSCLC,and the treatment of KRAS mutated lung cancer has been very difficult until major breakthroughs have been made in recent years.Src homology 2(SH2)-containing protein tyrosine phosphatase 2(SHP2)is a new target for KRAS mutated carcinoma.SHP2 is required for the growth of KRAS mutant NSCLC.Considering the role of SHP2 in epithelial tumor cells and immune cells,SHP2 may play a key role in the immunotherapy of KRAS mutated tumors,affecting the clinical efficacy.In this study,we focused on the expression of SHP2 and its predictive and prognostic significance in the treatment of KRAS mutant NSCLC patients with immune checkpoint inhibitors(ICIs).We further explored the tumor immune environment and analyzed the correlation between SHP2 and immune cells.Methods: This study is divided into two parts.In the first part,91 patients with advanced KRAS mutated lung adenocarcinoma were collected.The basic clinical data,gene mutation characteristics and survival analysis of advanced KRAS mutated lung adenocarcinoma were analyzed by next-generation sequencing(NGS)and immunohistochemistry(IHC)methods.In the second part,61 patients with KRAS mutated lung adenocarcinoma treated with immunotherapy were enrolled.Using NGS,IHC and multiple immunofluorescence cytochemistry(mIFC),we analyzed the expression of SHP2,phospho-SHP2(pSHP2)and programmed cell death-ligand 1(PD-L1)in KRAS mutant lung adenocarcinoma.The expression level was evaluated in tumor cells and immune cells.mIFC was conducted to simultaneously analyze the molecular biomarkers in each of two panels: SHP2,CD4,CD8,CD68 and CKs(panel 1),and CD8,PD-L1,programmed cell death protein 1(PD-1),T cell immunoglobulin and mucin domain-containing protein 3(TIM3)and CKs(panel 2).Results: The first part: the mutation rate of KRAS subtype G12 C,G12D and G12 V is 33.0%,20.9% and 15.4% respectively.There is no difference in survival analysis between different KRAS subtypes.IHC staining results showed that the positive rate of the expression level of PD-L1≥1% was 63.8%.Subgroup analysis showed that the expression level of PD-L1 in KRAS G12 C mutant lung adenocarcinoma is higher than non-G12 C mutant patients.The second part:this part included 61 KRAS mutant NSCLC patients underwent immunotherapy.SHP2 was heterogeneously expressed in tumor cells and immune cells and 25(78.1%)of the 32 patients were highly expressed(H-score≥10).The expression of SHP2 were positively correlated with pSHP2.It showed that stromal SHP2(s-SHP2)was higher in patients with PD-L1≥50%(P=0.039).There was no significant difference of SHP2 in difference smoking status,KRAS mutant subtypes(G12C vs G12 X vs others)and co-occurring mutated genes(KRAS+LKB1 vs KRAS+TP53 vs KRAS+CDKN2A/B vs KRAS alone).Using mIFC,s-SHP2 was positively correlated with stromal CD8(s-CD8),stromal CD4(s-CD4),stromal CD68(s-CD68)and stromal PD-L1(s-PD-L1).Patients with high SHP2 expression accounted for 100.0% of partial response(PR),80.0% of stable disease(SD)and 50.0% of progress disease(PD).High SHP2 expression was associated with longer progression-free survival(PFS)and overall survival(OS)(P<0.001,P=0.013).What is more,patients with both high SHP2 and PD-L1 expression had longer PFS(P<0.001).Conclusion: The expression levels of PD-L1 in KRAS G12 C and non-G12 C subgroup are statistically different,which provides a preliminary basis in order to further explore the treatment effect of KRAS mutant NSCLC with different mutation subtypes and PD-L1 level.In advanced KRAS mutant NSCLC treated with ICI,high expression of SHP2 may predict the treatment effect of immunotherapy.Our study showed that SHP2 may function in both tumor cells and immune cells in KRAS mutant NSCLC,warranting further study on the potential diverse effects of SHP2 inhibition on these cells in tumor immune environment. |
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