Laurey Comeau

Bio: Laurey Comeau is an academic researcher from University of North Carolina at Chapel Hill. The author has contributed to research in topics: Phagocytosis & Complement receptor. The author has an hindex of 1, co-authored 1 publications receiving 2319 citations.

Complement-dependent phagocytosis as a regulator of antibody-dependent cellular cytotoxicity

Abstract: While monoclonal antibodies (mAb), such as αCD20, have significantly improved patient outcomes for B cell malignancies, patient responses vary and drug resistance can occur. One proposed limitation is the reduction of innate immune effector functions such as antibody dependent cellular phagocytosis (ADCP) – the principal cytotoxic mechanism for many mAb-based therapeutics. ADCP is mediated by Fcγ Receptor- and complement-dependent pathways (FcγR-ADCP and cADCP, respectively). However, our lab has shown that the capacity of macrophages (Mϕ) to engulf mAb opsonized targets is finite and after brief period of engorgement, Mϕ enter a phase of negligible phagocytic activity termed hypophagia. We have previously described the mechanisms that negatively regulate FcγR-ADCP, but complement-induced hypophagia is less understood. To begin to characterize complement-induced exhaustion, we used live cell imaging to measure mAb opsonized thymocyte engulfment by primary mouse Mϕ in the presence absence of complement. Preliminary data suggest that cADCP kinetics and cytotoxic capacities are distinct from FcγR-ADCP; however, both lead to a hypophagic state that impinges on future target cell clearance. Furthermore, Mϕ refractory to additional FcγR-ADCP still phagocytose through complement receptors up until the cADCP pathway also becomes exhausted. Published data from our lab also show that FcγR driven hypophagia involves surface receptor downregulation, but interestingly, there is no reduction in complement receptor surface levels following cADCP-induced hypophagia. Therefore, a better understanding of cADCP and the mechanistic overlap with FcγR-ADCP is critical to optimizing mAb therapy by minimizing immune cell exhaustion. Supported by grants from NIH (T32 AI007496, 26A1)

Cellular senescence: when bad things happen to good cells

Abstract: Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

Shelterin: the protein complex that shapes and safeguards human telomeres

Abstract: Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.

How Shelterin Protects Mammalian Telomeres

Abstract: The genomes of prokaryotes and eukaryotic organelles are usually circular as are most plasmids and viral genomes. In contrast, the nuclear genomes of eukaryotes are organized on linear chromosomes, which require mechanisms to protect and replicate DNA ends. Eukaryotes navigate these problems with the advent of telomeres, protective nucleoprotein complexes at the ends of linear chromosomes, and telomerase, the enzyme that maintains the DNA in these structures. Mammalian telomeres contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage response and regulates telomere maintenance by telomerase. Recent experiments, discussed here, have revealed how shelterin represses the ATM and ATR kinase signaling pathways and hides chromosome ends from nonhomologous end joining and homology-directed repair.