LLT1-CD161 Interaction in Cancer: Promises and Challenges

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.

Mining the multifunction of mucosal-associated invariant T cells in hematological malignancies and transplantation immunity: A promising hexagon soldier in immunomodulatory

“…The natural cytotoxicity receptor CD161 (NK1.1 in mice) is generally expressed in NK cells and 24% of T cells including both γδ and αβ TCR-expressing subsets, natural killer T cells (NKT), MAIT cells, monocytes, and DCs ( 44 , 82 , 101 ). The single CLEC2D gene encoding LLT1 is identified as a ligand of CD161 ( 82 , 101 ).…”

“…The natural cytotoxicity receptor CD161 (NK1.1 in mice) is generally expressed in NK cells and 24% of T cells including both γδ and αβ TCR-expressing subsets, natural killer T cells (NKT), MAIT cells, monocytes, and DCs ( 44 , 82 , 101 ). The single CLEC2D gene encoding LLT1 is identified as a ligand of CD161 ( 82 , 101 ). Restricted to hematopoietic cells, LLT1 is not expressed on the surface of resting PBMCs but can be transiently expressed on activated B cells, dendritic cells, T cells, and NK cells ( 44 , 82 , 83 ).…”

“…Restricted to hematopoietic cells, LLT1 is not expressed on the surface of resting PBMCs but can be transiently expressed on activated B cells, dendritic cells, T cells, and NK cells ( 44 , 82 , 83 ). Some tumors of hematopoietic origin are also detected by LLT1 expression ( 75 ), which is highly expressed by germinal center (GC) B cells and is maintained in the group of non-Hodgkin’s lymphomas that derive from GC B cells ( 82 , 83 ). These include Burkitt lymphomas, follicular lymphomas, and GC-derived diffuse large B cell lymphomas ( 82 , 83 ).…”

“…Some tumors of hematopoietic origin are also detected by LLT1 expression ( 75 ), which is highly expressed by germinal center (GC) B cells and is maintained in the group of non-Hodgkin’s lymphomas that derive from GC B cells ( 82 , 83 ). These include Burkitt lymphomas, follicular lymphomas, and GC-derived diffuse large B cell lymphomas ( 82 , 83 ). In addition, Freeman G et al reported LLT1 on nodular lymphocyte-predominant Hodgkin lymphomas, and LLT1 triggering may play a key role in GC reactions, promoting B cell activation and the downregulation of CXCR4 ( 84 ).…”

Identification of CD161 expression as a novel prognostic biomarker in breast cancer correlated with immune infiltration

“…Accordingly, identifying the factors that affect the dynamic changes of TILs at the gene level is crucial for targeted BC treatment and improved prognosis outcomes. CD161, encoded by killer cell lectin-like receptor B1 (KLRB1), is a C-type lectin-related type II transmembrane protein expressed on NK cells, NKT cells and subsets of CD8 + and CD4 + T cells (Braud et al, 2022). It was identified as favorable prognostic gene in most human cancers (Braud et al, 2018;Duurland et al, 2022).…”