Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

Li, Dapeng; Brackenridge, Simon; Walters, Lucy; Swanson, Olivia; Harlos, K.; Rozbeský, Daniel; Cain, Derek W.; Wiehe, Kevin; Scearce, Richard M.; Barr, Maggie; Mu, Zekun; Parks, Robert; Quastel, Max; Edwards, Robert J.; Wang, Yunfei; Rountree, Wes; Saunders, Kevin O.; Ferrari, Guido; Borrow, Persephone; Jones, E Y; Alam, S. Munir; Azoitei, Mihai L.; Gillespie, Geraldine M.; McMichael, Andrew J.; Haynes, Barton F.

doi:10.1038/s42003-022-03183-5

Cited by 17 publications

(17 citation statements)

References 82 publications

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“…The surface expression of HLA-E requires binding to the MHC-I leader sequence, and HLA-E surface expression and a nity for NKG2A vary depending on the type of leader peptide that is bound (Battin, Kaufmann, et al 2022, Matsunami, Miyagawa, et al 2002. Antibodies that bind HLA-E leader peptide complexes enhance NK cell cytotoxicity (Li, Brackenridge, et al 2022). HLA-E surface expression is also affected by tapasin, TAP, and β 2 M, which are involved in movement to the cell surface (Braud, Allan, et al 1998, Lee, Goodlett, et al 1998, Lo Monaco, Sibilio, et al 2008.…”

Section: Discussionmentioning

confidence: 99%

Monalizumab efficacy correlates with HLA-E surface expression and NK cell activity in head and neck squamous carcinoma cell lines

Lee

Keam

Park

et al. 2022

Preprint

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Purpose NKG2A, an inhibitory receptor expressed on NK cells and T cells, leads to immune evasion by binding to HLA-E expressed on cancer cells. Here, we investigated the relationship between HLA-E surface expression on head and neck squamous cell carcinoma (HNSCC) cell lines and the efficacy of monalizumab, an NKG2A inhibitor, in promoting NK cell activity. Methods Six HNSCC cell lines were used as target cells. After exposure to IFN- γ, HLA-E surface expression on HNSCC cell lines was measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy donors and isolated NK cells were used as effector cells. NK cells were stimulated by treatment with IL-2 and IL-15 for 5 days, and NK cell-induced cytotoxicity was analyzed by CD107a degranulation and 51Cr release assays. Results We confirmed that HLA-E expression was increased by IFN-γ secreted by NK cells and that HLA-E expression was different for each cell line upon exposure to IFN-γ. Cell lines with high HLA-E expression showed stronger inhibition of NK cell cytotoxicity, and efficacy of monalizumab was high. Combination with cetuximb increased the efficacy of monalizumab. In addition, stimulation of isolated NK cells with IL-2 and IL-15 increased the efficacy of monalizumab, even in the HLA-E low groups. Conclusion Monalizumab efficacy was correlated with HLA-E surface expression and was enhanced when NK cell activity was increased by cetuximab or cytokines. These results suggest that monalizumab may be potent against HLA-E-positive tumors and that monalizumab efficacy could be improved by promoting NK cell activity.

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Section: Discussionmentioning

confidence: 99%

Monalizumab efficacy correlates with HLA-E surface expression and NK cell activity in head and neck squamous carcinoma cell lines

Lee

Keam

Park

et al. 2022

Preprint

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“…HLA-E, the ligand of NKG2A, is lowly expressed on almost all cell surfaces in human tissues, displays limited polymorphism, and presents peptides derived from the leader sequences of the classical MHC class I molecules HLA-A, HLA-B, and HLA-C [34,35]. Thus, the expression of HLA-E is directly related to the number of HLA-I molecules in a given cell, and NKG2A acts as a sensor to assess the net overall expression of HLA-I molecules on a target cell.…”

Section: Feature γδ T Cells αβ T Cellsmentioning

confidence: 99%

NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

Cazzetta

Depierreux

Colucci

et al. 2023

Cancers

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Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Current challenges associated with the enhancement of ICI effects are increasing the fraction of responding patients through personalized combinations of multiple ICIs and overcoming acquired resistance. This requires a complete overview of the anti-tumor immune response, which depends on a complex interplay between innate and adaptive immune cells with the tumor microenvironment. The NKG2A was revealed to be a key immune checkpoint for both Natural Killer (NK) cells and T cells. Monalizumab, a humanized anti-NKG2A antibody, enhances NK cell activity against various tumor cells and rescues CD8 αβ T cell function in combination with PD-1/PD-L1 blockade. In this review, we discuss the potential for targeting NKG2A expressed on tumor-sensing human γδ T cells, mostly on the specific Vδ2 T cell subset, in order to emphasize its importance and potential in the development of new ICI-based therapeutic approaches.

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“…Under physiological conditions, the affinity between HLA-E and CD94/NKG2A is significantly higher than that between HLA-E and CD94/NKG2C (28). Upregulation of HLA-E expression can protect target cells from being killed by NK cells (29). HLA-G and HLA-E have been found to be abnormally expressed in autoimmune diseases, viral infections and inflammation (30)(31)(32).…”

Section: Physiological Function and Structure Of Hlamentioning

confidence: 99%

Human leukocyte antigen and tumor immunotherapy (Review)

Liu

Mou²,

et al. 2023

Int J Oncol

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Malignant tumors seriously endanger human health and life, and restrict economic development. Human leukocyte antigen (HLA) is the expression product of the human major histocompatibility complex, which, at present, is the most complex known polymorphic system. The polymorphism and expression of HLA molecules have been demonstrated to be associated with the occurrence and development of tumors. HLA molecules can regulate the proliferation of tumor cells and inhibit antitumor immunity. In the present review, the structure and function of HLA molecules, the polymorphism and expression of HLA in tumor tissue, the roles of HLA in tumor cells and tumor immunity, and the potential clinical application of HLA in tumor immunotherapy are summarized. The overall aim of the present review is to provide relevant information for the development of antitumor immunotherapies involving HLA in the clinic. Contents 1. Introduction 2. Physiological function and structure of HLA 3. HLA polymorphism and cancer 4. Function of HLA in tumor immunity 5. Clinical significance of HLA in tumor immunotherapy 6. Future perspectives

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Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

Cited by 17 publications

References 82 publications

Monalizumab efficacy correlates with HLA-E surface expression and NK cell activity in head and neck squamous carcinoma cell lines

Monalizumab efficacy correlates with HLA-E surface expression and NK cell activity in head and neck squamous carcinoma cell lines

NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

Human leukocyte antigen and tumor immunotherapy (Review)

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