Biology subjects

Chacon, J.

Publications and source records attributed to Chacon, J..

3 recordsLinked to original sources

bioRxiv2021

Systematic analysis of CD39, CD103, CD137 and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs

The detection of tumor-specific T cells in solid tumors is integral to the interrogation of endogenous antitumor responses and to the advancement of downstream therapeutic applications, such as checkpoint immunotherapy and adoptive cell transfer. A number of biomarkers are reported to identify endogenous tumor-specific tumor infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39, however a direct comparison of these molecules has yet to be performed. Here, we evaluate these biomarkers in primary human high-grade serous ovarian tumor samples using single-cell mass cytometry to characterize and compare their relative phenotypic profiles, as well as their response to autologous tumor cells ex vivo. CD137+, PD-1+, CD103+, and CD39+ TILs are all detectable in tumor samples with CD137+ TILs being the least abundant. PD-1+, CD103+, and CD39+ TILs all express a subset of CD137+ cells, while CD137+ TILs highly co-express the aforementioned markers. CD137+ TILs exhibit the highest expression of cytotoxic effector molecules, such as IFN{gamma} and Granzyme B, compared to PD-1+, CD103+ or CD39+ TILs. Removal of CD137+ TILs from PD-1+, CD103+, or CD39+ TILs results in lower secretion of IFN{gamma} in response to autologous tumor stimulation, while CD137+ TILs highly secrete IFN{gamma} in an HLA-dependent manner. CD137+ TILs exhibited an exhausted phenotype with CD28 co-expression, suggestive of antigen recognition and receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1+, CD103+, and CD39+ TILs are mainly derived from a subset of TILs expressing CD137, implicating CD137 is a more selective biomarker for naturally occurring tumor-specific TILs.

immunology↗

bioRxiv2020

RNA-binding protein Elavl1/HuR is required for maintenance of cranial neural crest specification

While neural crest development is known to be transcriptionally controlled via sequential activation of gene regulatory networks (GRNs), recent evidence increasingly implicates a role for post-transcriptional regulation in modulating the output of these regulatory circuits. Using available single cell RNA-sequencing datasets from avian embryos to identify potential post-transcriptional regulators, we found that Elavl1, which encodes for an RNA-binding protein with roles in transcript stability, was enriched in the premigratory cranial neural crest. Perturbation of Elavl1 resulted in premature neural crest delamination from the neural tube as well as significant reduction in transcripts associated with the neural crest specification GRN, phenotypes that are also observed with downregulation of the canonical Wnt inhibitor Draxin. That Draxin is the primary target for stabilization by Elavl1 during cranial neural crest specification was shown by RNA-sequencing, RNA-immunoprecipitation, RNA decay measurement and proximity ligation assays, further supporting the idea that the downregulation of neural crest specifier expression upon Elavl1 knockdown was largely due to loss of Draxin. Importantly, exogenous Draxin rescued cranial neural crest specification defects observed with Elavl1 knockdown. Thus, Elavl1 plays a critical a role in the maintenance of cranial neural crest specification via Draxin mRNA stabilization. Together, these data highlight an important intersection of post-transcriptional regulation with modulation of the neural crest specification GRN.

developmental biology↗

bioRxiv2017

The spatial and metabolic basis of colony size variation

Spatial structure impacts microbial growth and interactions, with ecological and evolutionary consequences. It is therefore important to quantitatively understand how spatial proximity affects interactions in different environments. We test how proximity influences colony size when either Escherichia coli or Salmonella enterica are grown on different carbon sources. The importance of colony location changes with species and carbon source. Spatially-explicit, genome-scale metabolic modeling predicts colony size variation, supporting the hypothesis that metabolic mechanisms and diffusion are sufficient to explain the majority of observed variation. Geometrically, individual colony sizes are best predicted by Voronoi diagrams, which identify the territory that is closest to each colony. This means that relative colony growth is largely independent of the distance to colonies beyond those that set territory boundaries. Further, the effect of location increases when colonies take-up resource quickly relative to the diffusion of limiting resources. These analyses made it apparent that the importance of location was smaller than expected for experiments with colonies growing on sugars. The accumulation of toxic byproducts appears to limit the growth of large colonies and reduce variation in colony size. Our work provides an experimentally and theoretically grounded understanding of how location interacts with metabolism and diffusion to influence microbial interactions.

ecology↗