HLA-E, A Novel Immune Checkpoint
Immune checkpoint
The immune surveillance theory states that the immune system can constantly detect and eliminate abnormal cells that appear in the body. Similarly, the immune system can target and kill certain tumor cells through the cancer immunity cycle (CIC). However, tumor cells persist in the body constantly, which has puzzled researchers for some time. In 2006, Allison [1] proposed the concept of immune checkpoints, referring to programmed death receptors and their ligands, which exist in the immune system and regulate immune system signals.
In general, all important targets that can affect the immune response are immune checkpoints. For example, PD-1 and CTLA-4, which won the Nobel Prize in 2018, have immunosuppressive functions. Now, researchers have identified a new immune checkpoint, HLA-E.
A new immune checkpoint: HLA-E
Recently, a team from West China Hospital of Sichuan University published a cover research paper entitled “Immune checkpoint HLA-E: CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance” in Cancer Cell [2].
In this article, the team found a new immune checkpoint between circulating tumor cells (CTC) and NK cells, HLAE, and elaborated a new mechanism for CTC to evade the surveillance of NK cells through immune checkpoint molecules on HLA-E: CD94-NKG2A [2].
Circulating tumor cells (CTCs): "seeds" for distant metastasis
In 1869, Ashworth first proposed the concept of circulating tumor cells (CTCs) [3], which currently refer to all kinds of tumor cells existing in peripheral blood. Blood circulation is the main way for tumors to spread from the primary lesion to distant organs [4].
In this process, CTCs act as "seeds," undergoing five stages of invasion, intravasation, circulation, extravasation, and colonisation through the bloodstream, eventually leading to the development of malignant tumors (Figure 1).
Discovery and verification：HLA-E:CD94-NKG2A
To investigate the mechanism of CTCs metastasis, blood samples were collected from the primary tumor, liver metastases and the hepatic portal vein (HPV) of patients with pancreatic ductal adenocarcinoma. Single-cell sequencing (scRNA-seq) and other technologies were used to analyze their transcriptomic features and gene expression differences (Figure 2).
The results showed that a major interaction between CTCs and NK cells was observed in the blood circulation, with HLA-E and CD94-NKG2 having the strongest immune interaction between CTCS and NK cells (Figure. 3 A).
Further research found that the majority of NK cells harbor this immune suppressive receptor NKG2A. And the expression levels of HLA-E on CTCs are higher than that in tumor cells from solid lesions (Figures 3B–3D). Thus, the up-regulated interaction between NKG2A and HLA-E in HPV is potentially driven by increasing levels of HLA-E molecules [2].
Whether or not CTCs escaped from NK cell surveillance through the HLA-E: CD94-NKG2A checkpoint was then functionally investigated by NK cytotoxicity assay in vitro. To validate this immune checkpoint function in vivo, we recapitulated CTC-mediated metastasis by tail-vein injecting the luciferase-tagged mouse PDAC cell KPC, which intrinsically expresses H2-T23, the mouse homolog protein molecule of human HLA-E. In vitro and in vivo analyses showed that CTC and NK cells interacted with HLA-E: CD94-NKG2A via immune checkpoint molecules. Disruption of this interaction by blocking NKG2A or knocking down HLA-E expression enhanced NK-mediated tumor-cell killing in vitro and prevented metastasis in vivo (Figure 4).
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Mechanism: CTC up-regulates the immune checkpoint molecule HLA-E by platelet-derived RGS18
To illuminate how CTCs mobilize HLA-E expression, researchers evaluated the differentially expressed genes that potentially positively correlated with the expression level of HLA-E. An almost exclusive expression of RGS18 was observed in CTCs rather than in tumor cells from primary and metastatic lesions. It is well known that CTCS is usually covered by platelets, which are the main source of RGS18 protein [6].Taken together, signaling exploration indicates that RGS18 promotes the expression of HLA-E through the AKT- GSK3b-CREB1 axis. RGS18 overexpression significantly reduces the overall survival of liver metastasis mice (Figure 5).
Mechanism: As long as CTCs intravasate into blood vessels, they adhere to and uptake platelets that carry RGS18. The RGS18 inhibits the activation of phosphorylation AKT in host cells, which stabilizes GSK3b protein by suppressing GSK3b phosphorylation at Ser9. The GSK3b protein promotes the nucleus translocation of CREB1 by phosphorylation of CREB1 at Ser133. CREB1 binds the SXY site in the promoter region of the HLA-E gene in the nucleus, and up-regulates HLA-E expression and translocation on the surface of CTCs. The cell surface HLA-E interacts with CD94-NKG2A on NK cells, which activates the intracellular phosphatase SHP1 and suppresses the cytotoxic activity of NK cells [2].
Immune checkpoint blockade (ICB)
Immune checkpoint blockade (ICB) therapy, refers to the immune checkpoint blockade therapy based on programmed death receptor and its ligand, which enhance the host immune system's aggression against tumor cells by inhibiting the combination of the two, releasing immunosuppressive regulation and restoring the tumor-specific cytotoxicity of T lymphocytes [7][8]. ICB has brought tremendous changes to the treatment of many types of cancer. In the past few years, the FDA has approved 9 monoclonal antibody drugs that block immune checkpoints against PD-1 and CTLA-4, including 7 monoclonal antibodies against PD-1/PD-L1 and 2 monoclonal antibodies against CTLA-4, for more than 20 indications. These include metastatic melanoma, non-small cell lung cancer, renal cancer, hepatocellular carcinoma, etc. (Table 1) [9].
In recent years, some new immune checkpoint molecules including TIM-3, VISTA, and LAG-3 have been introduced into the study. For example, Many clinical trials (such as NCT03470922) have evaluated different blocking methods of LAG 3 combined with anti-PD-1 therapy as potential new ICBs [10]. Relatlimab? was finally approved by the US FDA for the first time in March 2022 for the treatment of melanoma, becoming the first anti-LAG-3 approved inhibitor.
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