Biology subjects

Hammer, Q.

Publications and source records attributed to Hammer, Q..

3 recordsLinked to original sources

bioRxiv2024

Human NK cell responses to the SARS-CoV-2 Spike269-277 peptide YLQPRTFLL

Natural killer (NK) cells act as the first line of defense against virus infections. The effector functions of human NK cells are controlled by inhibitory and activating receptors, including NKG2A and NKG2C, which recognize peptides presented by HLA-E. Recent studies have suggested that the SARS-CoV-2 Spike269-277 peptide YLQPRTFLL may modulate NK cell activity. Here, we show that the YLQPRTFLL peptide is poorly presented by HLA-E. Functional interrogation further revealed that loading of target cells with YLQPRTFLL did not affect the effector functions of NKG2A+ nor NKG2C+ NK cells. Our findings thus indicate that the Spike269-277 peptide YLQPRTFLL has a limited influence on human NK cell responses.

immunology↗

bioRxiv2023

Targeting HLA-E Positive Cancers with a Novel NKG2A/C Switch Receptor

HLA-E is overexpressed by approximately 80% of solid tumors, including malignant glioblastoma, and is emerging as a major checkpoint for NKG2A+ CD8+ T cells and NK cells in the tumor microenvironment and circulation. This axis operates side-by-side with PD-L1 to shut down effector responses by T and NK cells. Here, we engineered a novel chimeric A/C switch receptor, combining the strong HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. We found that A/C Switch-transduced NK and T cells displayed superior and specific cytotoxic function when challenged with tumor cells exhibiting medium to high HLA-E expression. Furthermore, A/C Switch-expressing human T cells demonstrated enhanced anti-tumor function in a xenograft model of glioblastoma. Importantly, the activity of the modified T cells was governed by an equilibrium between A/C Switch transduction level and HLA-E expression, creating a therapeutic window to safeguard against on-target off-tumor toxicities. Indeed, normal cells remained insensitive to A/C Switch engineered T cells even after pre-treatment with IFN-{gamma} to induce HLA-E expression. We propose that this novel A/C switch receptor may operate alone to control tumor cells expressing high levels of HLA-E or in combination with other engineered specificities to overcome the suppressive NKG2A/HLA-E checkpoint.

immunology↗

bioRxiv2023

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Allogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection, although absence of B2M triggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligands CD54 and CD58 on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion of CD54 and CD58 in B2M-deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cells in vitro and in vivo without affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.

immunology↗