LLT1-CD161 Interaction in Cancer: Promises and Challenges.

Veronique M. Braud,Claire Germain,Luciana Petti,Roxane Elaldi,Aïda Meghraoui-Kheddar,Fabienne Anjuère

doi:10.3389/fimmu.2022.847576

Abstract

The success of immune checkpoint therapy in cancer has changed our way of thinking, promoting the design of future cancer treatments that places the immune system at the center stage. The knowledge gained on immune regulation and tolerance helped the identification of promising new clinical immune targets. Among them, the lectin-like transcript 1 (LLT1) is the ligand of CD161 (NKR-P1A) receptor expressed on natural killer cells and T cells. LLT1/CD161 interaction modulates immune responses but the exact nature of the signals delivered is still partially resolved. Investigation on the role of LLT1/CD161 interaction has been hampered by the lack of functional homologues in animal models. Also, some studies have been misled by the use of non-specific reagents. Recent studies and meta-analyses of single cell data are bringing new insights into the function of LLT1 and CD161 in human pathology and notably in cancer. The advances made on the characterization of the tumor microenvironment prompt us to integrate LLT1/CD161 interaction into the equation. This review recapitulates the key findings on the expression profile of LLT1 and CD161, their regulation, the role of their interaction in cancer development, and the relevance of targeting LLT1/CD161 interaction.

Highlights

Natural killer (NK)-cell receptors (NKRs) are found expressed on the surface of NK cells and T cells where they contribute to regulate the threshold of activating and inhibitory signals, actively participating in the regulation of immune responses
We previously identified a cross-talk between dendritic cells (DC), NK and CD4+ T cells in lymph nodes and a role of CD4+ T cells secreting IL-2 in the activation of NK cells [78]
We propose that lectin-like transcript 1 (LLT1)/CD161 interaction contributes to these processes, LLT1 being induced on mature DC upon activation and CD161 being upregulated on NK cells and T cells by IL-12 secreted by mDC

Summary

Introduction

Natural killer (NK)-cell receptors (NKRs) are found expressed on the surface of NK cells and T cells where they contribute to regulate the threshold of activating and inhibitory signals, actively participating in the regulation of immune responses. LLT1 Expression on Tumor Cells Modulates Immunity in Cancer Expression of LLT1 has been investigated in several human cancers and was found expressed by tumor cells and by immune cells in the TME.

Results

Conclusion