ILT4 Predicts Immunosuppressive T Cell Infiltration In Lung Squamous Cell Carcinoma

Among cancers,the malignant tumor with the highest mortality and highest incidence is lung cancer.In the past 40 years,traditional radiotherapy and chemotherapy have been the main treatment for lung cancer,but the efficacy is not satisfactory.The 5-year survival rate of advanced patients is less than 21%.Among lung cancers,lung squamous cell carcinomas(LUSC)is one of the most important subtypes of non-small cell lung cancer.Tumor infiltrating lymphocytes(TILs)are an important part of the tumor immune microenvironment and participate in the anti-tumor immune response in the tumor immune microenvironment.FOXP3 is a specific transcription factor for Tregs.It can not only control the phenotype of Treg,but also maintain the immune function of Treg.In the tumor microenvironment(Tumor microenvironment,TME),Tregs are inhibitory test factors,and Tregs can reduce the ability of T lymphocytes to kill tumor cells,which is closely related to the eradication of tumors.Therefore,the study of T lymphocyte subsets in the tumor microenvironment is very important for tumor immunotherapy.In the immunoglobulin family,ILT4 is a kind of inhibitory immunoglobulin transcript receptor,which is mainly expressed in the innate cells of the myeloid lineage.In recent years,studies have shown that ILT4 is expressed in various types of tumor cells such as non-small cell lung cancer,breast cancer,leukemia,pancreatic cancer,and esophageal cancer,and is related to malignant biological behaviors such as tumor cell proliferation,invasion and metastasis.In addition,ILT4 is widely expressed in Myeloid-derived suppressor cells(MDSC),which can enhance the M2 polarization of tumor-associated macrophages(TAM)and promote the formation of tumor immunosuppressive microenvironment.ILT4 can promote the activation and activation of CD4+ T cells and induce the differentiation of Th2,which greatly promotes the formation of tumors,it will be of great significance to study the tumor microenvironment regulated by ILT4.In summary,ILT4 is mainly expressed in myeloid cells,and is also highly expressed in a variety of tumor cells.It is an immunosuppressive molecule and is closely related to the malignant biological behavior of malignant tumor cells.However,the immunomodulatory effect of ILT4 expressed in tumor cells has not been reported yet.Therefore,this study mainly analyzed and explored the relationship between the expression of ILT4 in tumor cells and the infiltration of T cells and the distribution of different subgroups,and clarified the impact of ILT4 on the tumor immunosuppressive microenvironment,and finally achieve the goal of using ILT4 as a new target of immunotherapy for patients with lung squamous malignant tumors and a new biomarker for monitoring prognosis.ObjectivesAnalyze the expression of ILT4 in lung squamous cell carcinoma,study whether ILT4 predicts inhibitory T cell infiltration,explore the relationship between LIT4 and the spatial distribution of T cell subsets,analyze the relationship between ILT4 and the prognosis of patients with lung squamous cell carcinoma,and clarify the regulatory effect of ILT4 on the tumor immunosuppressive microenvironment of patients with lung squamous cell carcinoma.Methods1.The pathological specimens of 80 patients with lung squamous cell carcinoma were collected from the Department of Pathology of Jinan Central Hospital.The clinical data was collected through the inpatient system,and the survival information of the enrolled patients was collected by telephone inquiries and inpatient data.2.Use immunohistochemical staining methods to detect the positive expression of CD3,CD4,CD8,FOXP3,and ILT4 in the patients,analysis of the positive expression of the above factors in tumor nests and tumor stroma;combined immunohistochemistry results and patient survival curves to analyze the correlation between the expression of ILT4 andthe clinical prognosis of patients with lung squamous cell carcinoma.3.Finally,analyze the relationship between the distribution density of ILT4 and the expression of the above-mentioned T lymphocyte subgroup molecules in tumor nests and stroma,and explore the influence of the different expressions of ILT4 and T lymphocytes on the survival and prognosis of patients with lung squamous cell carcinoma.ResultsILT4 is highly expressed in lung squamous cell carcinoma,and is low or not expressed in normal tissues adjacent to the cancer.Its positive expression is related to the patient’s poor survival and TNM stage and has no obvious correlation with tumor lymph node metastasis.In addition,the high expression of ILT4 is often accompanied by a decrease in tumor-infiltrating T lymphocytes.Further analysis of T cell subsets showed that with the high expression of ILT4 in the tumor,the infiltration proportion of CD8-positive T cells in the tumor nest was decreased,while the infiltration proportion of Treg cells was increased,and there was no significant difference between the two in the interstitial infiltration proportion,and the infiltration proportion of CD4-positive T cells did not change.This proves that the regulation of T cell subsets by ILT4 is independent of CD4,but related to CD8 and Treg.According to its more spatial distribution in the cancer nest and less in the stroma,it can be speculated that ILT4 may regulate T cell immunity by direct contact inhibition between cells,and thus play a role in inhibiting T cell immune function.The combination(high ILT4 expression,low CD8expression)/(high ILT4 expression,high Treg expression)predicts a worse survival outcome in patients with lung squamous cell carcinoma.Thus,the combination of ILT4 with CD8 and Treg has a higher predictive value for patient survival than any single marker.ConclusionIn lung squamous cell carcinoma,tumor-derived ILT4 molecules predict infiltration of immunosuppressive T cell subsets and may regulate T lymphocyte subsets through direct contact inhibition.This indicates that we have found a new prognostic biomarker for patients with lung squamous cell carcinoma--ILT4,and ILT4 may become a new target in immunotherapy of lung squamous cell carcinoma.Moreover,compared with any single marker,the combination of ILT4 with CD8 and Treg has a higher value in evaluating and predicting survival in patients with lung squamous cell carcinoma.