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[44]
was first described and cloned by our lab in human NK cells . Cross-linking of the LLT1 receptor on NK
[45]
cells induces the production of IFN-γ without activation of the cytolytic pathway . Our lab, confirmed
by others, also identified the NK cell inhibitory receptor NKRP1A (CD161) as the ligand for LLT1 and
implicated that LLT1 expressed on other cells could inhibit NK cell function [46,47] . LLT1 is encoded by the
CLEC2D gene, which produces five different isoforms through alternative splicing. Isoform 1 of LLT1
interacts with the NKRP1A (CD161) receptor. Isoforms 2 and 4 stay in the endoplasmic reticulum and
associate with LLT1 to form homodimers or heterodimers. Unlike LLT1 expressed on the cell surface,
Isoforms 5 and 6 are soluble forms of LLT1 [48,49] . As a C-type lectin-like receptor, LLT1 is composed of three
domains: a transmembrane domain, a stalk region, and the extracellular carbohydrate recognition domain,
[7]
which is responsible for recognition . B cells, NK cells, T cells, and activated dendritic cells also express LLT1
on the cell surface [48,49] . The crystal structure of LLT1 demonstrated it is highly glycosylated and when it forms
a homodimer at the cell surface it serves as a ligand for the NKRP1A receptor on NK cells [46,47,50,51] . NKRP1A
+
is encoded by KLRB1 and CD4 T cells, invariant NKT cells, and γδ-T cells have also been shown to express
[49]
NKRP1A . In mice, CLEC2D encodes the protein Ocil/Clr-b, which interacts with NKR-P1B/D [52-54] .
LLT1 AS AN IMMUNOTHERAPEUTIC TARGET FOR BREAST CANCER AND PROSTATE
CANCER
NK cells, B cells, T cells, and activated dendritic cells express LLT1 [46,48] . Monoclonal antibody blocking of
[45]
LLT1 could enhance the IFN-γ production of NK cells, but no differences in cytotoxicity have been seen .
Increased expression of LLT1 was observed after Toll-like receptor induced activation of B cells and dendritic
[49]
cells, which led to NK cell inhibition via LLT1 - NKRP1A interaction . Inhibition of NK cell function
through LLT1 has been observed on human malignant glioma cells, and immune crosstalk with B cells and
monocyte-derived dendritic cells [8,49,55] . Identification of a specific marker to enhance the ability of NK cells
to recognize TNBC cells and prostate cancer cells provides a promising way for clearance of cancer cells.
Previously, our lab studied the expression of LLT1 on TNBC and prostate cancer, and the results showed
higher expression of LLT1 on TNBC cells compared to normal cells. Monoclonal antibody blocking of LLT1
[9]
enhanced NK cell cytotoxicity and TNBC cells lysis . In addition to higher surface expression of LLT1 on
TNBC cells, our studies also demonstrated higher intracellular and surface expression of LLT1 in the prostate
cancer cells compared with normal prostate cells. Blocking the interaction between LLT1 and NKRP1A
[41]
increased NK cell cytotoxicity against prostate cancer cells . In addition to blocking the inhibitory signal,
anti-LLT1 mAb may activate ADCC (antibody dependent cell mediated cytotoxicity) function of NK cell
[56]
against breast cancer and prostate cancer [Figure 1]. Pasero et al. showed that highly effective NK cells
are associated with better prognosis in metastatic prostate cancer patients. Collectively, we demonstrate
that monoclonal antibodies to enhance NK cell activation may provide a promising treatment to target and
potentially prevent breast and prostate cancer metastasis. Santos-Juanes’ newest study showed higher LLT1
expression was contributed to the risk of neck cutaneous squamous cell carcinoma (cSCC) nodal metastasis,
[57]
which implicates LLT1 may also be a potential target to block cSCC nodal metastasis . Similar results have
also been seen in mice; inhibition of NKRP1B: Clr-b axis could enhance the NK cell-mediated immune
[52]
surveillance to oncogenic transformation . Due to the important role of LLT1 in tumor progression and
metastasis, monoclonal antibody blocking of LLT1 to enhance NK cell cytotoxicity may provide a novel
treatment to prevent tumor metastasis.

CONCLUSION
Tumor recurrence and metastasis is associated with chemotherapy resistance, which greatly enhances
the mortality in breast and prostate cancer [3,58] . NK cell-mediated immunotherapy could provide specific
recognition of tumor cells and overcome the resistance from chemotherapeutic drugs. LLT1, an inhibitory
ligand, is widely expressed on several cancer cell lines. Our lab has demonstrated higher expression of LLT1
on TNBC and prostate cancer cells and increased lysis of cancer cells after blocking LLT1 with monoclonal
antibodies. These results suggest LLT1 may offer a potential target for breast and prostate cancer treatment.