The Significance Of Siglec-15,CD8,FOXP3,PD-L1 Expression In Resected Non-small Cell Lung Cancer

Background:Siglec-15(S15)is one of the members of siglec family,which is widely expressed in many kinds of inflammatory tumors.It is another important mechanism of tumor immune escape besides programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)pathway.S15 represents a new generation of immune checkpoint inhibitor.However,the associations of tumor Siglec-15 expression with clinicopathological characteristics,outcomes of non–small-cell lung cancer(NSCLC),and tumor-infiltrating lymphocytes(TILs)in tumor microenvironment(TME)have so far been unclear.Methods:We enrolled 324 patients with NSCLC who had undergone surgical resection.Multiplex-immunofluorescence(IF)staining on tissue microarrays(TMAs)for Siglec-15,Cluster of Differentiation 8(CD8),fork head box P3(FOXP3),cytokeratin(CK),and 4?,6-diamidino-2-phenylindole(DAPI)were performed and analyzed using in Form software.We also tested for programmed death-ligand 1(PD-L1)in TMAs on Dako autostainer.Then we analyzed the association of these markers with both clinicopathological characteristics and overall-survival(OS)rates.Results:Siglec-15 expression was more frequent in lung adenocarcinoma(LUAD)than lung squamous-cell carcinoma(LUSC)(P=0.004).Siglec-15~+tumor cells'density was positively correlated with that of stromal CD8~+T cells(P<0.001).Tumor CD8~+T cells'density significantly increased in patients?60 years(P=0.001)and PD-L1–positive group(P=0.002),decreased with stage(P=0.031)and tumor size(P=0.041).Tumor FOXP3~+T cells'density decreased with tumor size(P=0.014).Stromal FOXP3~+T cells were denser in male patients(P=0.014),smokers(P=0.002),and LUSC patients(P<0.001);this density decreased with stage(P=0.019)and tumor size(P=0.027).Tumor PD-L1 expression increased with tumor size(P=0.034)and was more common in LUSC patients(P=0.006).A COX hazard proportion model analysis showed that patients in early T stage(hazard ratio[HR],0.406;95%confidence interval[CI],0.296–0.555;P<0.001),in early N stage(HR,0.655;95%CI,0.442–0.971;P=0.035),who had low PD-L1 expression(HR,0.646;95%CI,0.426–0.979;P=0.039),and who received adjuvant chemotherapy(HR,0.537;95%CI,0.401–0.718;P<0.001)had longer OS rates compared opposite factors.Conclusion:Our research showed that Siglec-15 expression was closely related to the clinicopathological factors of non-small cell lung cancer.Siglec-15 expression was more frequent in LUAD.And it was positively correlated with the density of CD8~+stromal T cells.However,it was not associated with OS in resected NSCLC.Since Siglec-15 expression is significantly increased in different tumor pathological histology compared with PD-L1,it may be more suitable for LUAD patients and is a complementary for immunotherapy based on PD-L1.As another important mechanism of tumor immune escape,further exploration of the association between Siglec-15expression and tumor microenvironment is of great significance for the treatment of patients with non-small cell lung cancer.