CD94 Immune Checkpoint Molecule for Drug Development

Overview of CD94 Immune Checkpoint

CD94 immune checkpoint belongs to immune checkpoints of NK cell, which is an unvarying chain receptor, possessing the ability to assemble into an activating heterodimer alongside NK group 2 member C (NKG2C) or E, alternatively into an inhibitory heterodimer coupled with NK group 2 member A (NKG2A). NKG2A (referred to as CD159 as well) and CD94 represent inhibitory receptors characterized by their heterodimeric nature within the C-type lectin family. These receptors specifically discern the MHC-I molecule HLA-E, serving as a ligand and expressing on the surface of NK cells and CD8⁺ T cells. Notably, the CD94-NKG2A complex and its corresponding HLA-E ligands exhibit a lack of polymorphism.

Fig. 1 Structural insight into the complex formed by NKG2A, CD94, and HLA-E.¹

CD94 as an Immune Checkpoint Participating in Signal Pathway

Restoration of effector functions in NK cells and T cells in preclinical cancer models through modulation of the CD94/NKG2A immune checkpoint.
CD94 can form dimers with the NKG2 protein on the cellular surface. Activation of CD94-NKG2A in conjunction with peptide-bound HLA-E induces phosphorylation of the intracellular immunoreceptor tyrosine-based inhibitory motifs within NKG2A. This event leads to the transmission of an inhibitory signal, suppressing conflicting cues originating from activating receptors, including NKG2D or the T cell receptor (TCR). Thus, while the engagement of TCRs with conventional MHC class I molecules is essential for the activation of CD8⁺ T cells, the interaction involving CD94-NKG2A and HLA-E curtails the activation potential of both NK cells and T cells.

Fig. 2 The immune regulatory checkpoint mediated by CD94/NKG2A-HLA-E.²

The activating molecule corresponding to the inhibitory receptor NKG2A is NKG2C. This molecule also creates a heterodimeric structure with CD94 and connects with the signaling adaptor DAP12. The inhibitory NKG2A/CD94 complex engages with HLA-E-peptide complexes, leading to a significant reduction of NF-κB-activation.

Fig. 3 Interactions of NKG2A/CD94 complex with HLA-E participate in the NF-κB pathway.³

Case Study

CD94 expression patterns in responsive T and NK Cells. (Fang, et al., 2021)

Fig. 4 CD94 expression patterns in responsive T and NK Cells.⁴
The discoveries in this research revealed a diverse spectrum of CD94 expression within T/NK-cell malignancies, with certain instances displaying levels that indicated susceptibility to therapeutic interventions targeting CD94.

Qa-1b/NKG2A constitutes an immune checkpoint in ICB-Induced CD8+ T cell responses. (Dubrot, et al., 2022)

Fig. 5 Qa-1b/NKG2A/CD94 constitutes an immune checkpoint in ICB-Induced CD8⁺ T cell responses.⁵
NKG2A (Klrc1) and CD94 (Klrd1) labeling predominantly identified effector, fatigued, and proliferating CD8⁺ T cells, concurrently expressing genes linked to cytotoxicity and exhaustion. In comparison to NK cells, effector CD8⁺ T cells exhibited elevated NKG2A expression, corroborated through flow cytometry.

Services at Creative Biolabs

Creative Biolabs brings significant expertise to the realm of pharmaceutical investigation, aimed at tackling this undertaking. This effort aligns synergistically with a decade-long history of scholarly collaboration, aiming to delve into the role of CD94 checkpoint molecular in the context of cancer. Our prominently highlighted offerings are related to tailored crafting of immune checkpoint protein repertoires, antibody generation targeting immune checkpoints, formulation of peptides targeting immune checkpoints, etc.

Creative Biolabs has established a comprehensive spectrum of offerings aimed at the scrutiny of the CD94 checkpoint molecule. This emerges as a hot therapeutic locus, orchestrating immune kinetics within the genesis of an array of conditions, including T-cell lymphomas and leukemias, alongside remarkably heterogeneous disorders in NK-cell lineages. For further information, we invite you to contact us and share your specific requirements.

References

Kaiser, Brett K., et al. "Structural basis for NKG2A/CD94 recognition of HLA-E." Proceedings of the National Academy of Sciences 105.18 (2008): 6696-6701.
Creelan, et al. "The NKG2A immune checkpoint—a new direction in cancer immunotherapy." Nature Reviews Clinical Oncology 16.5 (2019): 277-278.
Battin, Claire, et al. "NKG2A-checkpoint inhibition and its blockade critically depends on peptides presented by its ligand HLA‐E." Immunology 166.4 (2022): 507-521.
Fang, Hong, et al. "CD94 expression patterns in reactive and neoplastic T-cell and NK-cell proliferations." Leukemia Research 108 (2021): 106614.
Dubrot, Juan, et al. "In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer." Nature Immunology 23.10 (2022): 1495-1506.

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