| Objective:Immune checkpoint is one of the hotspots of immunotherapy.Studies have shown that mismatch repair protein deficiency patients are sensitive to checkpoint inhibitor therapy.Lymphocyte activation gene 3(LAG-3)is an immune checkpoint molecule expressed on T cells.The increased expression of LAG-3 in colorectal cancer is related to the deficiency of MMR,but has not been reported in endometrioid adenocarcinoma.Forkhead box P3(FoxP3)is the signature molecule of regulatory T cells.LAG-3~+FoxP3~+regulatory T cells are highly expressed in multiple solid tumors and are associated with poor prognosis,but are rarely reported in endometrial cancer.In this study,the expressions of LAG-3,FoxP3 and MMR protein in endometrioid adenocarcinoma were compared.To investigate the correlation between LAG-3 and MMR protein expression,in order to determine whether patients with MMR deficiency of endometrial cancer are the benefit population of anti-LAG-3immunotherapy.Methods:Two hundred and three cases of endometrioid adenocarcinoma with complete clinicopathological data from 2016 to 2017 were selected and the expression of MMR protein was detected by immunohistochemistry.In addition,36 cases of deficient in MMR(dMMR)and 36 cases of complete MMR protein expression(proficient in MMR,pMMR)are selected to compose the paired data in a 1:1 ratio,and the expressions of FoxP3 and lAG-3 are detected by immunohistochemistry.The correlation between MMR expression,number of tumor infiltrating lymphocytes,tumor size,diffuse growth pattern,histological grade and lymph node metastasis was analyzed.The correlation between FoxP3 and LAG-3 expression was analyzed.The subcellular localization of FoxP3 and LAG3 was detected by immunofluorescence stain The expressions of FoxP3,LAG3 and MMR in endometrial carcinoma were analyzed by TCGA database.Results:(1)In this study,56 cases(27.6%)in 203 cases were dMMR.Most of the sites of dMMR endometrial carcinoma were located in the uterine horn,showing a local growth pattern(P<0.05).PMMR mostly occurred in the uterine body filled with uterine cavity,with diffuse growth(P<0.05).The age of onset of dMMR patients was younger than that of pMMR patients,but the difference was not statistically significant.There was no significant correlation between MMR expression and tumor invasion depth,histological grade and lymph node metastasis(P>0.05).(2)Compared with pMMR,dMMR patients highly expressed LAG-3 in both tumor infiltrating lymphocytes(TIL)and interstitial infiltrating lymphocytes while FoxP3 was highly expressed in interstitial infiltrating lymphocytes(P<0.01).(3)The increase in LAG-3expression is related to the diffuse growth pattern of the tumor,which often covers the entire uterine cavity(P<0.01).The maximum diameter of the tumors with high expression of FoxP3 and LAG-3 was large(P<0.01).There was no significant correlation between lAG-3 and FoxP3 expression and age,tumor site,tissue differentiation,depth of invasion,lymph node metastasis,ER,PR or P53.(4)LAG-3was expressed on the membrane surface of lymphocytes and FoxP3 was expressed in the nucleus of lymphocytes.Immunofluorescence confirmed the co-expression on the same cell.(5)In the TCGA database,there was a positive correlation between LAG3and FoxP3 mRNA expression,and the mRNA expression level of LAG3 increased in MSI patients and MSS patients,while the mRNA expression level of LAG3 increased with tumor stage,and there was no significant correlation between LAG3 and FoxP3mRNA expression and prognosis of patients.Conclusion:LAG-3 protein highly expressed in the tissue of dMMR endometrioid adenocarcinoma,suggesting that anti-LAG-3 treatment is more likely to benefit patients with dMMR endometrioid adenocarcinoma.LAG-3 expression is correlated with FoxP3 expression and co-expressed in the same cell,suggesting that the mechanism of LAG-3 promoting immune escape may be related to FoxP3~+regulatory T cells.Therefore,dMMR patients with endometrioid adenocarcinoma may benefit from anti-LAG-3 treatment.The mechanism of anti-LAG-3 immunotherapy may be related to FoxP3~+regulatory T cells. |
