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that showed people with higher incidence of cancers have defective NK cell functions caused by gene
deficiency [25,26] . Additionally, tumor growth and metastasis were also observed in NK mutant mice or after
blocking NK cell activity by antibodies [27,28] . Two types of receptors are expressed on NK cells: inhibitory
receptors and activation receptors. Natural cytotoxicity receptor family, killer cell lectin-like receptor, and
CD16 comprise the majority of activation receptors expressed on NK cells [29,30] . The common characteristic
of these NK cell activation receptors is having a cytoplasmic immunoreceptor tyrosine-based activation
motif to mediate the activation signals. Unlike NK cell activation receptors, inhibitory receptors such as killer
cell immunoglobulin-like receptors and the heterodimer CD94-NK group 2A recognize and bind to self
MHC class I molecules and the inhibitory signals are mediated via cytoplasmic immunoreceptor tyrosine-
[31]
+
based inhibition motifs . In contrast with CD8 T cells, activation of NK cells does not require antigen
[32]
presenting cell priming or MHC restriction . NK cell activation is regulated by the balance from activation
[33]
and inhibitory receptor mediated signaling . Therefore, through multiple, simultaneous complex signaling
pathways, NK cells recognize and kill a broad range of tumor cells. For example, tumor specific antigen
interaction with activation receptors on NK cells, accompanied with lack of co-engagement of inhibitory
[34]
receptors, will lead to secretion of perforin and granzyme from NK cells to target tumor cells . Additionally,
it has been reported that some tumor cells have spontaneous loss of MHC class I expression as a mechanism
+
for CD8 T cell escape. NK cells, which do not require antigen presentation, are able to recognize and kill
[35]
MHC class I low tumor cells .
NK CELLS AND IMMUNOTHERAPY
Antibody dependent cell-mediated cytotoxicity (ADCC) is another primary function of NK cells and
is currently being investigated to be used in NK cell-mediated immunotherapy. NK cells use the CD16
(FcγRIII) receptor to bind with the Fc portion of antibodies bound to specific antigens on target cells and
[36]
induce NK cell cytotoxicity . Monoclonal antibodies (mAb) can also be used to block the interaction
between ligands and receptors on NK cells. We have shown that activating NK cells via surface receptor
CS1 (CD319, SLAMF7) enhanced the ability of NK cells to kill various tumor cells [37,38] . Several other
studies showed that CS1 is overexpressed on multiple myeloma (MM) and a humanized anti-CS1 mAb
(Elotuzumab/Empliciti) was approved as a break through drug for treatment for MM patients [39,40] . Our
lab has found overexpression of LLT1 ligand on TNBC and prostate cancer, which interacts with the NK
receptor NKRP1A (CD161) and inhibits NK cell cytotoxicity [9,41] . Thus, blocking inhibitory signals to NK
cells using monoclonal antibodies to LLT1 could enhance the lysis of prostate cancer and TNBC cells by NK
cells [9,41] .

+
Checkpoint inhibitors, which are traditionally used to promote CD8 T cell function, have also been
demonstrated to effect NK cell function. More specifically, NK cells express PD-1 and binding to PDL-1 on
target cells results in inhibition of NK cell function and more aggressive tumors. Blockade of PD-1 and PDL-1
[42]
with mAb results in the strong NK cell responses required for full immunotherapeutic effect .
In addition to checkpoint inhibitors, CARs (chimeric antigen receptor) can be engineered in NK cells or
NK cell lines. Binding of a CAR to a tumor associated antigen leads to a strong activating signal, which
[43]
triggers NK cell cytotoxicity . Currently, there are many clinical trials taking advantage of CAR NK cells.
One such trial (NCT03056339) utilizes a CAR specific for the tumor associated antigen CD19 coupled to the
costimulatory domains of CD28 and the zeta chain of the TCR/CD3 complex. Additionally, the retroviral
vector expresses IL-15 for optimal NK cell activation and the inducible caspase 9 (iC9; iCasp9) suicide gene.

LLT1 AND NKRP1A
LLT1, also known as CLEC2D (C-type lectin domain family 2 member D), OCIL (Osteoclast inhibitory
lectin), and CLAX (Lectin-like NK cell receptor), belongs to the C-type lectin-like receptor superfamily and