Biology subjects

Qie, Y.

Publications and source records attributed to Qie, Y..

4 recordsLinked to original sources

bioRxiv2024

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

cancer biology↗

bioRxiv2023

Use of dye sensitizers for increased photoacoustic mechanosensation

The photoacoustic effect refers to the generation of pressure waves in matter stimulated by light[1]. In the context of radiology (i.e., photoacoustic imaging) waves generated by pulsed laser light are detected by an ultrasound transducer[2-4]. It has been shown that photoacoustic waves produce a mechanical, tactile sensation in humans on bare skin[5]. In a series of psychophysical experiments, performed with both medical grade and off-the-shelf pulsed light systems, participants could detect, categorically describe, and discern the direction of travel of pulsed optical stimuli with the use of a dye as an optical absorber on the skin. To a large extent, the sensations were perceived as localized vibration on the glabrous surface of the fingers, when sensitized with the thin film of dye. This form of sensory stimulation demonstrates an enhanced non-contact, non-optogenetic, in situ activation of the mechanosensory system. This modality of sensation may provide a tool that leads to new insights in psychology, neuroscience, mechanobiology, and the health sciences. Finally, it has many advantageous characteristics for human interaction with artificial environments, as optical signals can be projected onto the skin across distances.

neuroscience↗

bioRxiv2023

CAR T-cell therapy- Paving the way for sensitized kidney transplant patients.

Anti-HLA donor specific antibodies have been extensively documented for their critical role in kidney transplant rejection and resulting adverse outcomes. Several approaches have been employed to desensitize these patients; however, none of these explored therapeutic approaches has exhibited enduring clinical benefits. In this study, we explore a novel strategy of utilizing chimeric antigen receptor T cells (CAR T-cells) to target B cells in sensitized kidney transplant recipients. Specifically, we investigate the potential of our innovative MC10029 CAR T-cells, which are designed to recognize the B cell activating factor receptor (BAFF-R). BAFF-R is predominantly expressed on mature B cells and plays a crucial role in their survival, as well as in the promotion of autoreactive B cell. Our data revealed that sensitized patients B cells exhibited high levels of BAFF-R expression. We have successfully generated patient-derived MC10029 CAR T-cells from 6 sensitized patients. All these patient-derived MC10029 CAR T-cells consistently exhibited antigen-specific cytotoxicity against autologous B cells, accompanied by the release of cytotoxic granules. We have recently obtained FDA approval of an Investigational New Drug application for MC10029 CAR T-cell therapy in B-cell hematological diseases. This significant milestone paves the way for the pioneering launch of a human clinical trial, marking the first-ever application of CAR T-cell therapy in sensitized patients waiting for life-saving organ transplants.

immunology↗

bioRxiv2022

Structural basis for BIRC6 to balance apoptosis and autophagy

Caspase-9 is the initiator caspase for the intrinsic apoptotic cell death pathway, and is critical to the activation of effector caspases during apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor of Apoptosis Protein (IAP) BIRC6/BRUCE/Apollon not only inhibits apoptosis, but also promotes ubiquitination of the key autophagic protein LC3 and inhibits autophagy. Here we show that BIRC6 forms an anti-parallel U-shaped dimer in a 3.6-[A] cryo-EM structure with multiple previously unannotated domains, including a ubiquitin-like domain, and discover that the mitochondria-derived pro-apoptotic factor Smac/DIABLO binds BIRC6 by interacting with one BIR domain, two carbohydrate-binding modules and two helices in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not caspase 9, for binding BIRC6. BIRC6 strongly inhibits cellular activity of caspase 9, but weakly suppresses that of caspase 3. Meanwhile, BIRC6 binds LC3 through an LC3-interacting region, probably following dimer disruption of this BIRC6 region. Deficiency in LC3 ubiquitination promotes autophagy and autophagic degradation of BIRC6, and inhibits apoptosis. Moreover, induction of autophagy promotes autophagic degradation of both procaspase-9 and active caspase-9, but not of effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

cell biology↗