Abstract
Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine–tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.
Highlights
Breast cancer is the most common cancer diagnosed in women worldwide, with an estimated 2.3 million new cases and 0.7 million deaths in 2020 [1]
We detected abundant killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4) expression on infiltrating natural killer cells (NK) cells in HER2 positive breast cancer tissues. These findings indicated that Human leukocyte antigen (HLA)-G/KIR2DL4 in immune microenvironment might play an important role in the progression of breast cancer and become a new target for breast cancer treatment
Paracrine TGF-b and IFN-g in breast cancer microenvironment can induce PD-1/ PD-L1 expression on NK cells and tumor cells, which might further enhance intercellular signaling that leads to immunosuppression. These findings demonstrated the applicability of combined human leukocyte antigen-G (HLA-G)/KIR2DL4 and PD-1/PD-L1 targeting in the treatment of trastuzumab-resistant breast cancer (Figure 1)
Summary
Breast cancer is the most common cancer diagnosed in women worldwide, with an estimated 2.3 million new cases and 0.7 million deaths in 2020 [1]. Five intrinsic subtypes of breast cancer were initially identified: Luminal-A, Luminal-B, HER2+, triple negative/basal like (TNBC) and normal like, which is based on the gene expression of estrogen receptor (ER), progesterone receptor (PR), and human. The conventional treatment options for patients with breast cancer include surgery, chemotherapy, radiotherapy, hormonal therapy and targeted therapy [3]. Increasing evidence has showed that breast cancer microenvironment is composed of tumor cells and of other different cell types, including endothelial cells, several stromal cell types, and immune cells [4]. Our recent study has showed that human leukocyte antigen-G (HLA-G) was a pivotal mediator of HER2 positive breast cancer resistance to trastuzumab and blockade of HLA-G can improve the antitumor activity of NK cells significantly [7]
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