The Relationship Between Mismatch Repair Deficiency And Tumor Immune Microenvironment In NSCLC

Objective:To discuss the relationship between mismatch repair deficiency and tumor immune microenvironment in non-small cell lung cancer(NSCLC), in order to provide a biomarker for the immunotherapy of NSCLC.Methods:1. 40 cases of NSCLC paraffin-embedded samples and corrusponding tissue samples were collected in Tianjin medical university cancer hospital. To examine the expression of mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 by IHC and to examine microsatellite locus D13S170, D9S162, D17S786 and D10S185 by PCR-SSCP to investigate the consistency of IHC and PCR-SSCP in examination of the status of mismatch repair system.2. 109 cases of NSCLC paraffin-embedded samples were collected in Tianjin medical university cancer hospital. To examine the expression of mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 and the immune cells infiltration to investigate the relationship of mismatch repair deficiency with tumor-infiltrating immune cells in non-small cell lung cancer.3. 24 cases of NSCLC fresh tissue samples were collected in Tianjin medical university cancer hospital. To examine the expression of mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 and the immune checkpoint molecules to investigate the relationship of mismatch repair deficiency with immune checkpoint molecules in non-small cell lung cancer.Results:1. To examine the status of mismatch repair system by IHC and PCR-SSCP, the results show that the consistent rate of both ways is 92%(P<0.001).2. To examine the infiltration of the immune cells in the groups of p MMR and d MMR by IHC, the results show that high numbers of CD3+, CD4+, CD8+,CD20+, CD68+, Foxp3+cells in d MMR group, among them CD3+, CD4+, CD8+,Foxp3+, CD68+ cells significantly increase in lung adenocarcinoma(P<0.001;P=0.027; P<0.001; P=0.046; P=0.012), and CD3+, CD8+cells significantly increase in squamous carcinoma of the lung(P=0.004; P=0.009).3. To examine the expression of immune checkpoints molecules PD-1, PD-L1,CTLA-4 and LAG-3 by flow cytometry, the results show that the expression levels of PD-1 and PD-L1 increase in CD8+T lymphocytes of d MMR group(P=0.033; P=0.024), but the similar results not in CD4+T lymphocytes. And there are no differences of the expression levels of CTLA-4 and LAG-3 between the groups of d MMR and p MMR.Conclusion:There is higher number of immune cells infiltration and higher expression of checkpoint molecules especially PD-1/PD-L1 in tumor-infiltrating T lymphocytes in d MMR-NSCLC. And these patients can get benefits from immune blockade therapy,especially for anti-PD-1 therapy. Finally the mismatch repair deficiency can serve as one biomarker for good objective response of immunotherapy in NSCLC...