| Background and Aims:Colorectal cancer(CRC)has been a serious public health burden in China and globally,with a high rate of morbidity and mortality.Despite the promotion of cancer screening and the improvement of people's health awareness,about a quarter of patients are diagnosed with synchronous metastases and?50%of cases suffer from metastases after initial radical surgery during long-term follow-up.For metastatic CRC,the use of conventional surgery,chemotherapy,ablative methods and targeted therapy has improved survival.However,the prognosis of metastatic CRC is still poor,with 5-year survival of less than 15%.Thus,there is an urgent need for new therapies to treat metastatic CRC patients.A large number of studies have verified that immunotherapy,including PD-1/PD-L1 inhibitors,has significantly improved the prognosis of metastatic CRC.However,only patients with deficient mismatch repair can benefit from immunotherapy,and this group only accounts for 5%of metastatic CRC.Thus,targeting other immune checkpoints may offer more immunotherapeutic choices for patients,who are excluded from current PD-1/PD-L1 inhibitor therapy.During the early stage of this study,we found B7-H3 to have the highest expression among B7-CD28 family members in CRC and B7-H3 expression was elevated in CRC tissues compared to normal mucosal tissues from TCGA database,indicating that B7-H3 may be a potential immunotherapy target.Here,the expression,prognostic significance and angiogenesis of B7-H3 was further investigated in our large CRC cohort and in vitro,laying the foundation for the later clinical transformation application.Methods:Patients diagnosed with CRC that were treated from 2010 to 2014 at the Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively obtained,and the corresponding HE-stained paraffin blocks were collected to construct the tissue microarrays.B7-H3,B7-H4,and PD-L1 protein levels and CD3+,CD8+,and CD45RO+T cells were evaluated in tissue microarrays,and the relationships between immune markers,patient characteristics,and survival outcomes were determined.In vitro,stable B7-H3 overexpression and knockdown CRC cells were constructed to explore the effect on angiogenesis of human umbilical vein endothelial cells(HUVECs).Results:A total of 805 patients were enrolled in this study,with the mean age of 58.3 years and 446(55.4%)males.The stage ?,?,?,? patients were 101(12.5%),241(29.9%),319(39.6%)and 144(17.9%)respectively.B7-H3(50.9%)was detected in more primary tumors than B7-H4(29.1%)or PD-L1(29.2%),and elevated B7-H3 expression was associated with advanced overall stage.Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors(6.3%,5.7%,respectively).Although discordant expression in primary tumors versus metastases was identified in over 16%of patients,B7-H3,B7-H4 and PD-L1 in primary tumors were positively correlated with their respective expression at metastatic sites(?>0.6;p<0.001).No significant relationships between B7-H4 and PD-L1 and survival were observed;however,B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival.A positive relationship between B7-H3 expression and high density of CD45RO T-cell was observed in primary tumors,whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration.In vitro,overexpression of B7-H3 promotes the angiogenesis of HUVECs,however,knockdown of B7-H3 can abolish this effect.Conclusions:Compared with B7-H4 and PD-L1,B7-H3 expression exhibited a higher prevalence and co-expression of B7-H3 with B7-H4 and PD-L1 was infrequent in primary tumors.In addition,B7-H3 expression in primary tumors correlated with their corresponding expression in metastatic sites.Moreover,B7-H3 expression in primary tumors was significantly related to advanced overall stage,worse prognosis,CD45RO T-cell infiltration and angiogenesis,supporting B7-H3 as a potential immunotherapeutic target in CRC patients. |
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