The Expression Of PD-L1,Siglec-15 And CSPG4 In Colorectal Cancer And Its Clinical Significance

Background: CRC is one of the most common digestive system malignancies worldwide,and its morbidity and mortality rank third and second in the world,respectively.According to the cancer report released by the National Cancer Center in 2016,the incidence and mortality of CRC in our country have maintained an upward trend.The occurrence and development of colorectal cancer involve multiple steps,in which immune escape plays an important role.Therefore,exploring the mechanism of colorectal cancer immune escape,finding biomarkers for early diagnosis,evaluating prognosis,monitoring recurrence and metastasis of colorectal cancer,and developing new immunotherapy targets are of great significance for improving the early diagnosis rate and development of colorectal cancer,carrying out precise treatment and improving prognosis.PD-1/PD-L1 is currently a hot spot in the study of T cell costimulatory pathways.The binding of PD-L1 and PD-1 promotes the phosphorylation of tyrosine in the immune receptor tyrosine conversion motif domain,resulting in the dephosphorylation of downstream protein kinases Syk and PI3 K,inhibits the activation of downstream AKT,ERK and other pathways,inhibits the transcription and translation of genes and cytokines required for T cell activation,and plays a negative role in regulating T cell activity.Thus promoting tumor occurrence,development and metastasis.Current studies have shown that PD-L1 overexpression in cancers such as hepatocellular,renal,esophageal,pancreatic,ovarian,and bladder cancers is associated with poor clinical outcomes,while PD-L1 expression in breast and silent Kerr cell carcinoma is associated with better clinical outcomes.There is still controversy about the expression and prognostic role of PD-L1 in colorectal cancer.Therefore,studying its expression in colorectal cancer may provide a reference for predicting prognosis and exploring therapeutic targets.Sialic acid-binding immunoglobulin-like lectin 15(Siglec-15)is a member of the Siglec family.Early studies identified it as a modulator of osteoclasts and could be a therapeutic target for osteoporosis.In recent years,Siglec-15 m RNA was found to be overexpressed in most cancers,such as breast cancer,bile duct cancer,esophageal cancer,pancreatic cancer,skin melanoma,gastric adenocarcinoma,thyroid cancer,and endometrial cancer.Siglec-15 expressed on tumor-associated macrophages may promote tumor immune evasion by inhibiting CD8+ T cell-mediated immune responses and increasing TGF-β secretion by interacting with DAP12 and Syk,thereby contributing to tumor immunosuppression formation of the microenvironment.Studies have shown that Siglec-15 is one of the pathways for tumor cells to escape the pursuit of immune cells and can be used as a new target for immunotherapy.Professor Lie Ping Chen et al.found that in the vast majority of PD-L1 negative tumors,Siglec-15 is the main immunosuppressive factor.The anticancer effect of this target is likely to be mutually exclusive with PD-1.That is to say: for the vast majority of tumors,there is no Siglec-15 with high PD-L1 expression;there is no PDL1 with high Siglec-15 expression.The expression of Siglec-15 is mutually exclusive with that of PD-L1,suggesting that it may be a key immune evasion mechanism in PD-L1-negative patients.At present,regarding the expression of Siglec-15 in colorectal cancer and its relationship with PD-L1,the relationship between Siglec-15 and prognosis is still unclear.Therefore,studying its expression in colorectal cancer may provide a reference for further exploring the immune escape mechanism of colorectal cancer and finding new therapeutic targets.CSPG4 is a type I single-channel transmembrane protein that belongs to the chondroitin sulfate proteoglycan family.CSPG4 can regulate the growth and development of perivascular cells in the tumor microenvironment,promote angiogenesis,promote tumor growth,adhesion,migration,invasion,EMT and chemotherapeutic drug resistance,and play an important role in the occurrence and development of tumors.CSPG4 is expressed in several different cancers and has been associated with poor prognoses,such as melanoma,leukemia,glioma,triple-negative breast cancer,head and neck cancer,and mesenchymal cancer.It is still unclear about the expression of CSPG4 in colorectal cancer.Therefore,studying its expression in colorectal cancer and its relationship with PD-L1 and Siglec-15 may provide a reference for predicting prognosis and therapeutic targets.Objective: To detect the expressions of PD-L1,Siglec-15,and CSPG4 in colorectal cancer tissues,and to analyze the relationship between the expression levels of PD-L1,Siglec-15,CSPG4 and clinicopathological features;to explore the relationship between the expressions PD-L1,Siglec-15 and CSPG4,and prognosis;further analyze the relationship between PD-L1,Siglec-15 and CSPG4 expression,to provide an experimental basis for exploring the mechanism of colorectal cancer immune escape,finding new targets for immunotherapy and biomarkers for prognosis detection.Methods: Taking a colorectal cancer tissue chip as the research object,the expressions of PD-L1,Siglec-15,and CSPG4 in 106 colorectal cancer tissues and adjacent tissues were detected by immunohistochemistry.The relationship between PD-L1,Siglec-15,and CSPG4 and clinicopathological characteristics and prognosis of colorectal cancer patients was analyzed,and the correlation of PD-L1,Siglec-15,and CSPG4 expression was further analyzed.Results:(1)The expression of PD-L1 in colorectal cancer tissues was higher than that in adjacent tissues,and the difference was statistically significant(P<0.05).The high expression of PD-L1 was associated with lymph node metastasis and TNM stage(P<0.05),but not with gender,tumor location,vascular tumor thrombus,nerve invasion,distant metastasis,and MMR(P>0.05).The mean survival time of the PD-L1 high expression group was not significantly different from that of the low PD-L1 expression group(P>0.05).The PD-L1 expression level was not related to the prognosis of colorectal cancer.(2)There was no significant difference in the expression level of Siglec-15 between colorectal cancer tissues and adjacent tissues,and Siglec-15 was not associated with gender,tumor location,vascular tumor thrombus,nerve invasion,lymph node metastasis,TNM stage,distant metastasis,and MMR(P >0.05).The mean survival time of the Siglec-15 high expression group was better than that of the low expression group(P<0.05),suggesting that high Siglec-15 expression was associated with a better prognosis.(3)The expression of CSPG4 in colorectal cancer tissues was higher than that in adjacent tissues,and the difference was statistically significant(P<0.05).CSPG4 was not associated with gender,tumor location,vascular tumor thrombus,nerve invasion,lymph node metastasis,TNM stage,distant metastasis,and MMR(P>0.05).The mean survival time of the CSPG4 high expression group was not significantly different from that of the low expression group(P>0.05),and the CSPG4 expression level was not related to the prognosis of colorectal cancer.(4)The expression of PD-L1 in colorectal cancer was negatively correlated with the expression of Siglec-15(r=-0.232,P=0.017);the expression of PD-L1 in colorectal cancer was positively correlated with the expression of CSPG4(r=0.235,P=0.015));Siglec-15 expression was not correlated with CSPG4 expression in colorectal cancer(r=-0.09,P=0.361).(5)The average OS of the PD-L1 low expression and Siglec-15 high expression group was better than that of the PD-L1 high expression and Siglec-15 low expression group,and the difference was statistically significant(P<0.05).(6)There was no significant difference in the average OS of colorectal cancer patients with different PD-L1 and CSPG4 expression levels among the four groups(P>0.05).Conclusion:(1)PD-L1 is highly expressed in colorectal cancer tissues and is positively correlated with lymph node metastasis and TNM staging.(2)The high expression of Siglec-15 is associated with better prognosis of patients and can be used as a monitoring index to judge the prognosis of colorectal cancer.(3)CSPG4 is highly expressed in colorectal cancer tissues.(4)The expression of PD-L1 in colorectal cancer was negatively correlated with the expression of Siglec-15,and positively correlated with the expression of CSPG4.(5)Low expression of PD-L1 and high expression of Siglec-15 are indicators of good prognosis in patients with colorectal cancer.