2.11 HHLA2 (HERV-H LTR-associating 2)
HHLA2 (HERV-H LTR-associating 2; Human endogenous retrovirus-H Long
repeat-associating 2; also called B7 homolog 5 [B7-H5]) is a member
of the B7 family of immune checkpoint molecules that has garnered
attention for its role in regulating immune responses, particularly in
the context of cancer immunotherapy. It is a type I transmembrane
glycoprotein that is expressed on various immune cells and tumor cells
within the TME [250]. The discovery of HHLA2 as an immune checkpoint
protein is relatively recent (1999) [251], and its precise functions
are still being elucidated. However, studies have shown that HHLA2 plays
a role in immune regulation by interacting with its receptors on T cells
and other immune cells. It is constitutively expressed on the surface of
human monocytes and can be induced on B cells [250]. HHLA2 molecule
is also highly expressed in tumor associated macrophages (TAMs)
[252].
HHLA2 interacts with KIR3DL3 (killer cell Ig-like receptor with
three Ig domains and a long cytoplasmic tail, also known as also known
as KIRC1, KIR44, and KIR3DL,) and TMIGD2 (T cell membrane
protein with immunoglobulin and ITIM domains 2) at different sites to
exhibit both inhibitory and stimulatory functions, respectively. Despite
the presence of TMIDG2, the inhibitory function mediated by the
KIR3DL3-HHLA2 interaction predominates. [253, 254]. Therefore,
tumors may escape immune surveillance through the KIR3DL3-HHLA2 pathway
by suppressing CD4 and CD8 T-cell activation and effector functions in
the presence of T-cell receptor signaling. This includes reducing T-cell
proliferation, cytokine production, and cytotoxic activity against tumor
cells. [254, 255]. KIR3DL3-HHLA2 pathway also inhibits the
cytotoxicity of an NK-cell [254].
In cancer, HHLA2 expression has been observed on various types of
tumors, including osteosarcoma [256], renal cell carcinoma
[257], pancreatic cancer [258, 259], melanoma [260],
hepatocellular carcinoma [261], ovarian cancer [262], gastric
cancer [263], colorectal cancer [264] and lung cancer [265].
Elevated levels of HHLA2 have been associated with poorer prognosis,
highlighting its role as a potential target for therapeutic intervention
[250, 256, 257, 261, 263, 264, 265, 266]. However, better survival
and prognosis is also reported with overexpression of HHLA2 in some
studies [252, 258, 260, 262, ].
Targeting HHLA2 with specific inhibitors or blocking antibodies
represents a novel strategy to enhance anti-tumor immunity. Considering
the beneficial role of the TMIGD2 receptor, an ideal therapeutic
approach would involve selectively blocking the interaction between
HHLA2 and KIR3DL3 [255]. Monoclonal antibody targeting the
HHLA2/KIR3DL3 pathway, which block the inhibitory activity of KIR3DL3
while preserving the immune-stimulatory effects of HHLA2 via TMIGD2 have
shown promising results in pre-clinical studies [253]. A study by
Wei et al. revealed that KIR3DL3 blockade inhibits tumor growth in
multiple humanized mouse models [255]. However, study by Wang et
al. showed (unexpected function ) targeting TMIGD2 signaling with
anti-TMIGD2 monoclonal antibodies diminishes leukemia stem cell
self-renewal and decreases leukemia burden in AML patient-derived
xenograft models, while having minimal impact on normal hematopoietic
stem and progenitor cells [267]. Clinical trials are underway to
evaluate the safety, efficacy, and therapeutic potential of HHLA2
inhibitors in various cancers. In July 2023, a multicenter
first-in-human study, (Phase I clinical trial, NCT06240728) commenced to
evaluate NPX887, a antagonistic immunoglobulin G1 (IgG1) monoclonal
antibody targeting HHLA2 (B7-H7)\ KIR3DL3 interaction.
This antibody aims to reactivate exhausted T and NK cells in
HHLA2-positive solid tumors. The trial focuses on recurrent or
metastatic solid tumors, including renal cell carcinoma (RCC), non-small
and small cell lung carcinoma, colorectal carcinoma (CRC), and TNBC.