Tumor-derived ILT5 and suppression of T cell immunity in non-small cell lung cancer.

Abstract

8531 Background: Immune checkpoint inhibitors targeting PD-(L)1 pathways have revolutionized the treatment of non-small cell lung cancer (NSCLC) since last decade. However, the efficacy is still limited because the immunosuppressive tumor microenvironment (TME) restricts ICI-primed T cell immunity. Therefore, it is quite crucial to block the potential mechanisms in inducing immunosuppression to improve ICI efficacy. Immunoglobulin-like transcript (ILT) 5 is an important immunosuppressive molecule expressed in a wide range of myeloid cells and predicts tumor progression. Our group was the first to report ILT5 expression in solid tumor cells (colorectal cancer). However, the expression and function of ILT5 in NSCLC are still unknown. Methods: ILT5 expression in NSCLC tissues and tumor cell lines was determined by PCR, western blotting and immunofluorescence. The impact of tumor-derived ILT5 on T-cell phenotypes and functions was evaluated using flow cytometry and immunofluorescence. ILT5-regulated downstream signals and molecules were determined by RNA sequencing, PCR, western blotting, and flow cytometry. Tumor transplantation and immunotherapeutic models were established in C57/BL6 and NSG mice to explore the effect of ILT5 on tumor progression and the synergies of ILT5 blockade with ICIs. Results: ILT5 is highly expressed in NSCLC cells, predicting poor patient survival. ILT5 induced CD8 + T cell exhaustion rather than senescence and apoptosis in the TME. Mechanistically, ILT5 upregulated PD-L1 through the activation of PI3K-AKT-mTOR signaling pathway, which in turn increased PD-1 expression in CD8 + T cells and induced their exhaustion. PIR-B (ILT5 orthlog in mice) overexpression in mice induced CD8 + T cell exhaustion and tumor growth in vivo, while PIR-B knockdown had the opposite effect. More importantly, inhibition of ILT5 synergistically enhanced the tumoricidal effect of PD-1 inhibitor in NSCLC immunotherapeutic models. Conclusions: Enriched ILT5 expression in NSCLC cells induces CD8 + T cell exhaustion via activation of PI3K-AKT-mTOR-PD-L1 pathway. ILT5 inhibition synergistically enhanced the efficacy of PD-1 inhibitor. Our findings identifies a novel mechanism for tumor immunosuppression and develops a promising strategy for improving ICI efficacy.