Dendritic Cell CTLA-4
As professional antigen presenting cells, dendritic cells balance immune activation and inhibition to maintain immune homeostasis. An important inhibitory molecule expressed by dendritic cells is Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Our lab has shown that DC CTLA-4 is expressed and secreted in extracellular vesicles (EVs) by mature DC. The inhibitory mechanism of action comes from the ability of these DC secreted CTLA-4+ EVs to bind to the co-stimulatory DC surface markers CD80 and CD86 to prevent T-cell activation. Therefore DC CTLA-4+ EVs act in a paracrine and autocrine fashion to downregulate immune responses. Additionally, siRNA ablation of DC CTLA-4 leads to increased efficacy of a DC vaccine to mount an anti-tumor response in various cancer models, suggesting that DC CTLA-4 modulation could be a rational strategy to improve DC vaccines. Our current DC CTLA-4 research focuses on identifying the gene regulation, and EV function of DC CTLA-4. Additionally, we will define the function of CTLA-4 by using DC conditional CTLA-4 mouse knockouts to characterize the in vivo function and sufficiency of DC CTLA-4.
Role of Dendritic Cell AIMp1 in Th1 cell polarization
The proper functioning of the Th1 mediated immune response is necessary for the host’s ability to fight off intracellular infections and cancer. The lack of an effective Th1 immune response results in increased susceptibility to infections and a reduced anti-tumor response, while an overactive Th1 response can lead to autoimmune diseases. After experiments showing that a knockout of aminoacyl t-RNA synthetase complex interacting multifunctional protein 1 (AIMp1) resulted in both a reduction in antitumor and antiviral immunity, we conclude that AIMp1 is necessary for proper Th1 polarization. Our focus is on elucidating the mechanisms of DC-specific AIMp1 regulation of Th1 polarization.
Dendritic cell vaccines can be generated via ex vivo differentiation followed by loading of MHC molecules with antigens of interest. When MHCI and MHCII are loaded with peptides that share regions of 100% amino acid sequence identity, the resulting DCs drive significantly improved Th1-mediated antitumor and anti-viral immune responses. We have identified two critical mediators of this phenomenon, CTLA-4 and AIMp, whose expression respectively limit and facilitate Th1 immunity in the context of homologous loading. Our lab works to delineate the mechanisms which govern homologous loading, subsequent expression of CTLA-4 and AIMp1 as well as the resultant T cell responses observed.
A novel subset of cytotoxic memory CAR-T cell therapy for solid tumors
We have recently characterized the therapeutic potential of a novel subset of CD8+ T cells against aggressive solid tumors and infections. Marked by the expression of NK1.1 in mice and CD161 in humans, this unique subset is characterized by enhanced cytotoxicity, tissue homing, persistence and memory characteristics, ideal for immunotherapy of aggressive solid tumor malignancies. In experimental murine model of HER2+ PDAC, CAR-transduced CD8+CD161+ T cells killed the tumors faster and better than the standard CAR-T cells improving overall survival. Efforts are underway to translate these to human trials and-also to generate pre-clinical data against other aggressive models like neuroblastoma
Phase I clinical Trials against PDAC and GBM
We are actively enrolling patients for our Phase I clinical Trials against PDAC and GBM. Homologously loaded dendritic cells are manufactured in the GMP facility of the Center for Cell and Gene Therapy, Baylor College of Medicine. After rigorous QA/QC testing, the vaccines are infused to the patients in a dose escalation study.
Bioinformatic Analysis of Immunologic Phenomena
Briana acts as the computational and statistical analyst of the lab. Her projects span immunologic topics both in and out of the lab. These include the lab projects on CTLA-4 and AIMp1 as well as collaborations researching antibody responses and tumor immunology.