Overexpressed immunoglobulin-like transcript (ILT) 4 in lung adenocarcinoma is correlated with immunosuppressive T cell subset infiltration and poor patient outcomes

BACKGROUND: The poor response to current PD-1/PD-L1 inhibitors in lung cancer patients requires development of novel immunotargets. Immunoglobulin-like transcript (ILT)4 is an immunosuppressive molecule mainly expressed in myeloid innate cells. Recent studies showed that ILT4 was highly expressed in multiple malignant cells and regulated tumor biologies including proliferation, invasion and metastasis. However, the immunomodulatory role of tumor cell-derived ILT4 is unclear. Here we aimed to analyze the correlation of tumor cell ILT4 expression with T cell infiltration and subset distribution, illustrate ILT4-regulated immunosuppressive microenvironment, and raise tumor cell-derived ILT4 as a novel immunotherapeutic target and prognostic biomarker for lung adenocarcinoma (LUAD) patients. METHODS: We collected the tissue samples and corresponding clinicopathological data from 216 primary LUAD patients. Using immunohistochemical staining and public database analyses we investigated the relationship between ILT4 expression and different T cell subset density as well as patient outcomes. RESULTS: Enriched ILT4 expression in tumor cells of LUAD tissues indicated reduced T cell infiltration in the tumor microenvironment (TME), advanced diseases and poor patient overall survival (OS). Further T cell subset analyses revealed that ILT4 expression was correlated with decreased CD8(+)T cell and increased Treg frequency in both cancer nest and stroma, but not with altered CD4(+)T cell frequency. High ILT4 level combined with low CD8(+)T cell/high Treg density predicted markedly poorer clinical outcomes compared with any of these biomarkers alone. CONCLUSIONS: Tumor cell-derived ILT4 is correlated with immunosuppressive T cell subset infiltration and poor clinical outcomes, and might be a potential immunotherapeutic target and prognostic biomarker for LUAD patients. Combined ILT4 expression and CD8(+) T cell/Treg frequency in tumor infiltrating lymphocytes (TILs) are stronger predictors for patient outcomes.