Biology subjects

Fullerton, B. T.

Publications and source records attributed to Fullerton, B. T..

2 recordsLinked to original sources

bioRxiv2026

A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.

genomics↗

bioRxiv2022

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

cancer biology↗