Lately, the world-leading haematology journal the Lancet Haematology published a report [1], suggesting that administering multiple infusions of CYAD-01 without preconditioning exhibited both favorable efficacy and safety in the treatment of patients with recurrent/refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or multiple myeloma (MM). CYAD-01 is an NKG2D receptor-based CAR-T cell therapy that NKG2D receptor binds eight ligands (MICA, MICB; ULBP1-ULBP6) that are overexpressed in a wide range of haematological malignancies.
ULBP1, a member of NKG2D ligands, many findings implied that it is highly expressed in a variety of hematologic and solid tumors. Therefore, the use of NKG2D CAR-T targeting approach is expected to enhance the anti-tumor activity against tumor cells with high expression of ULBP1. Today, let’s explore the new opportunities of ULBP1 as a potential member of NKG2D ligands in cancer immunotherapy!
The NKG2D ligands (NKG2DLs) recognized by NKG2D, mainly include UL16 binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6) and MHC class I-related chain proteins (MICA and MICB) [2]. Under physiological circumstances, NKG2DLs are expressed at low levels on the surface of healthy cells. However, when cells undergo stress due to factors such as infection or malignant transformation, NKG2DL expression is up-regulated (Figure 1) [3]. This up-regulation allows for the formation of the NKG2D-NKG2DL complex. NK cells have the ability to remove specific stressed cells, which is crucial to maintain tissue homeostasis [3].
Figure 1. NKG2DL expression was induced in cancer [3]
UL16-binding protein 1 (ULBP1) is a member of the NKG2D ligand family, also known as NKG2DL, which belongs to a novel family of MHC class I-related molecules. ULBP1 gene is located at 6q24.2-6q25.3, which encodes for a protein that possesses only the alpha 1 and alpha 2 immunoglobulin-like domains, no capacity to bind peptides or interact with beta 2-microglobulin. Despite this limitation, the ULBP1 protein still plays an important role in the immune system. It is anchored to the cell membrane via a GPI-linkage, which allows it to interact with other proteins and cells in its environment (Figure 2) [5].
ULBP1 has been shown to activate various immune cells, including NK cells, CD8+ T cells, and γδ T cells, by binding to a receptor NKG2D. Through this interaction, ULBP1 involves the detection and elimination of abnormal or infected cells. Notably, current findings indicated that NKG2D/ULBP1 plays a critical role in the targeting and killing of cancer cells via immune cells. This highlights the importance of ULBP1 as a potential therapeutic target for cancer immunotherapy [6].
Figure 2. Structure of NKG2DLs [5]
Many studies have shown that the NKG2D/NKG2DL system is important in treating cancer. The NKG2D/NKG2DL system prompts cancer cells to produce NKG2DL, which makes them more vulnerable to being destroyed by NK cells. This clearly demonstrates how the NKG2D/NKG2DL system is involved in immune protection against tumors, and therefore makes it a valuable target for immunotherapy (Click the article to know more "NKG2D, a Powerful Molecule Involved In CAR-T And Car-NK Cell Therapy"). However, the intricate mechanisms that underlie the induction of NKG2DL remain largely elusive.
A study for the first time reported functional properties of ULBP1. As a result, transcription factors Sp3 and Sp1 have significant influence on ULBP1 activity. Both in vitro and in vivo experiments demonstrated that these transcription factors bind to the CRE(1) site located in the minimal promoter of the ULBP1 gene. Collectively, the production of ULBP1 is strictly dependent on Sp1/Sp3 activity [7].
In addition, mutation or deletion of the Sp1/Sp3 binding site in HeLa and HEK293 cells remarkably inhibited ULBP1 promoter activity, which in turn affected the immune response to cancer or infected cells. The findings also suggested that ULBP1 expression may be influenced by AP-2α, which down-regulates ULBP1 expression in HeLa cells (Figure 3) [7].
Another study revealed that the NS3/4A protein of the hepatitis C virus restrained ULBP1 promoter. Furthermore, with an increase in the levels of NS3/4A protein expression, it was noted that the degree of inhibition became more significant [8]. Besides, IL15 can impede the infiltration of esophageal cancer cells via triggering the ULBP1/NKG2D signaling in NK cells [9-10].
Figure 3. ULBP1 transcriptional regulation model [7]
NKG2DL expression differs significantly in specific tumors or infected cells, indicating that distinct stimuli or pathological conditions may lead to varying NKG2DL expression. Multiple studies have shown a noticeable increase in the expression of ULBP1 in a range of tumor types such as leukemia, lymphoma, melanoma, breast cancer, lung cancer, and gastric cancer [11-13]. The binding of ULBP1 with NKG2D on T cells and NK cells triggers their cytotoxic activity against tumors.
In primary glioma cells, MICA, ULBP1, ULBP2, and ULBP3 expression are present, but MICB is rarely expressed [14-15]. In primary leukemia and malignant melanoma, ULBP was mainly expressed. In ovarian cancer cells, MICA, ULBP1, and ULBP3 are down-regulated, while ULBP2 is up-regulated [16-17].
In ovarian and head and neck squamous cancers, ULBP1 expression was positively correlated with patient survival [18-20]. Conversely, studies have shown that in colorectal and pancreatic cancers, ULBP1 expression levels are inversely correlated with patient survival [21-22]. Additional research has indicated that p53 may considerably increase the expression of ULBP1 and ULBP2 in cancer cells, thereby enhancing the killing effect of NK cells [23].
In leukemia or lymphoma, ULBP1 has been widely reported over-expressed. Studies have established that lymphoma cells expressing high levels of ULBP1 are more likely to be attacked by γδ T cells. The expression levels of ULBP1 varied widely among lymphoma patients, suggesting that ULBP1 may function as a biomarker for predicting the effectiveness of γδ T cell immunotherapy in treating certain individuals [24].
Several drugs that focus on ULBP1 are undergoing clinical trials (Table 1), including a CAR-T drug named CYAD-01 (also known as CAR-T NKG2D) developed by Celyad, Inc, which is currently in phase II of clinical trials. As noted earlier, CYAD-01 has shown promising results in the first patient with complete remission during a clinical trial aimed at relapsed refractory AML.
Furthermore, an anti-ULBP1 monoclonal antibody is currently in the drug discovery phase and is anticipated to initiate clinical trials in the upcoming years. The successful progress and implementation of these targeted drugs grounded on the NKG2D/NKG2DL system may provide novel opportunities for the treatment of multiple hematological and solid tumors!
Drug Name | Target | Mechanism of action | Drug Type | Indications | Institutes | R&D Status |
---|---|---|---|---|---|---|
CYAD-01 | ULBP1 | ULBP1 regulator | CAR-T |
Myeloproliferative disorders; Acute myeloid leukemia; Multiple myeloma; Myelodysplastic syndromes; Colorectal cancer; Liver metastases from colon cancer; Colon cancer. |
Dartmouth College; Ono Pharmaceutical Co., Ltd.; Celyad Oncology SA | Clinical Phase 2 |
Anti-NKG2DL gamma delta CAR-T cell therapy | ULBP1 | T-lymphocyte replacement; gene transfer; ULBP1 inhibitor | CAR-T | Colorectal cancer; nasopharyngeal cancer; tumor; prostate cancer; sarcoma; gastric cancer | CytoMed Therapeutics Ltd. | Clinical Phase 1 |
KYK-2.0 IgG1 (NCI) | ULBP1 | ULBP1 inhibitor | Monoclonal antibodies | / | / | Drug Discovery |
Table 1: ULBP1 Clinical Trials for Drug Development
To fully support researchers and pharmaceutical companies in their research on ULBP1 in multiple hematological and solid tumors, CUSABIO presents ULBP1 active proteins (CSB-MP887177HU ; CSB-MP887177HUj1-B) to support your research on the mechanism of ULBP1 or its potential clinical value (click for the full list of ULBP1 products: ULBP1 Proteins; ULBP1 antibodies).
ULBP1 proteins:
● Recombinant Human UL16-binding protein 1(ULBP1) (Active) (CSB-MP887177HU)
● Recombinant Human UL16-binding protein 1(ULBP1),Biotinylated (Active) (CSB-MP887177HUj1-B)
References
[1] Sallman, David A., et al. "CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory a cute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial." The Lancet Haematology 10.3 (2023): e191-e202.
[2] Lanier, Lewis L. "NKG2D receptor and its ligands in host defense." cancer immunology research 3.6 (2015): 575-582.
[3] Jones, Amber B., et al. "Regulation of NKG2D stress ligands and its relevance in cancer progression." Cancers 14.9 (2022): 2339.
[4] Baumeister, Susanne H., et al. "Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple MyelomaPhase I Trial of NKG2D-CAR T cells in AML/Myeloma." Cancer immunology research 7.1 (2019): 100-112.
[5] Wu, J., & Wang, X. (2011). NKG2D-Based Cancer Immunotherapy. inTech. doi: 10.5772/23523
[6] Cho, Hanbyoul, et al. "MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer." BMC cancer 14 (2014): 1-11.
[7] López-Soto, Alejandro, et al. "Transcriptional regulation of ULBP1, a human ligand of the NKG2D receptor." Journal of Biological Chemistry 281.41 ( 2006): 30419-30430.
[8] Ma, H. F., et al. "The construction of reporter plasmid of ULBP1 and preliminary studying on the influence of NS3/4A on transcription of ULBP1." Xi bao yu fen zi Mian yi xue za zhi= Chinese Journal of Cellular and Molecular Immunology 25.6 (2009): 483-485.
[9] Dong Liang, et al. "IL-15 inhibits migration and invasion of esophageal cancer cells by activating NK cell ULBP1/NKG2D signaling in co-culture system." Chinese Journal of Immunology 39.03: 466.
[10] Hu, Baoguang, et al. "Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1." Cancer Medicine 9.8 (2020): 2686-2697.
[11] Qi, Feng, et al. "Tumor mutation burden-associated LINC00638/miR-4732-3p/ULBP1 axis promotes immune escape via PD-L1 in hepatocellular carcinoma." Frontiers in Oncology 11 (2021): 729340.
[12] Textor, Sonja, et al. "Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2ULBP1 and ULBP2 Are Direct p53 Target Genes." Cancer research 71.18 (2011): 5998-6009.
[13] Nanbakhsh, Arash, et al. "c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis." Blood , The Journal of the American Society of Hematology 123.23 (2014): 3585-3595.
[14] Jung, Tae-Young, et al. "Immunological characterization of glioblastoma cells for immunotherapy." Anticancer research 33.6 (2013): 2525-2533.
[15] Choi, Haeyoun, et al. "Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands. "OncoImmunology 11.1 (2022): 2138152.
[16] Sutherland, Claire L., et al. "ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15." Blood 108.4 (2006): 1313 -1319.
[17] Morgado, Sara, et al. "NK cell recognition and killing of melanoma cells is controlled by multiple activating receptor-ligand interactions." Journal of innate immunity 3.4 (2011): 365-373.
[18] Cho, Hanbyoul, et al. "MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer." BMC cancer 14 (2014): 1-11.
[19] Carlsten, Mattias, et al. "DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells." Cancer research 67.3 (2007): 1317-1325.
[20] Saito, Hiroki, et al. "A combined lymphokine-activated killer (LAK) cell immunotherapy and adenovirus-p53 gene therapy for head and neck squamous cell carcinoma." Anticancer research 34.7 (2014): 3365-3370.
[21] Kim, So-Jung, et al. "COX-2- and endoplasmic reticulum stress-independent induction of ULBP-1 and enhancement of sensitivity to NK cell-mediated cytotoxicity by celecoxib in colon cancer cells." Experimental Cell Research 330.2 (2015): 451-459.
[22] Chen, Jiong, et al. "Expression and prognostic significance of unique ULBPs in pancreatic cancer." OncoTargets and therapy (2016): 5271-5279.
[23] Textor, Sonja, et al. "Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2ULBP1 and ULBP2 Are Direct p53 Target Genes." Cancer research 71.18 (2011): 5998-6009.
[24] Lanca, Telma, et al. "The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity." Blood, The Journal of the American Society of Hematology 115.12 (2010): 2407-2411.
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