Category: PAPERS

Published in Nature Biotechology (2020)

I was fortunate enough to be a co-author on this paper with the co-founder of Carisma Therapeutics, Mike Klichinsky. In this paper, we showed that macrophages could be transduced with a chimeric Ad5f35 adenovirus to express a first generation CAR. This CAR is active and causes the phagocytosis and killing of target postive tumor cells, while also stimulating pro-inflamatory cytokine release upon antigen stimulation. This promotes tumor clearance in vitro and in vivo, while also converting the TME from “cold” to “hot.”

Find this article on PubMed!

DOI: 10.1038/s41587-020-0462-y

Published in: Biophysical Journal (2019)

This paper, written by my collaborator Alex Buffone, extends the paradigm of upstream migration in immune cells to neutrophils. Previous studies had suggested that these cells did not migrate upstream on ICAM-1 like other immune cells. Through the use of blocking antibodies and engineered surfaces, we proved that these cells will migrate upstream if Mac-1 is blocked. We believe that Mac-1 acts as a sink for ICAM-1, which prevents the engagement of LFA-1 and the resulting upstream migration.

DOI: 10.1016/j.bpj.2019.08.044

Published in: Integrative Biology (2019)

In this paper, we took a previously published model of T cell trafficking and extended it to include the functions of kindlin-3, a protein which mediates the conversion of LFA-1 from an intermediate affinity form to the high affinity form used to arrest on the endothelium. Our simulations predicted that lymphocyte adhesion would be hypersensitive to the level of kindlin-3, which we then predicted through genetic perturbation of a model cell line along with comparisons to literature. Especially exciting for us was that the predictions were quantitatively accurate. This suggests that Adhesive Dynamics simulations can used to predict the effect of changing protein levels or kinetic constants on the ability of cells to adhere to endothelium.

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DOI: 10.1093/intbio/zyz024

Published in: Annals of Biomedical Engineering (2018)

This paper, which I am a second author on, was originally going to be about the forces exerted by dendritic cells under certain conditions. However, we found that on the force detectors the cells migrated differently compared to cells on a flat surface. What we found instead was evidence that dendritic cells can sense the geometry of the substrate they are on. For example, we found rings of actin around the tips of posts sticking up from the surface, but did not see similar rings on flat surfaces containing adhesive ligands. Overall, quite the interesting paper!

Find this article on PubMed!

DOI: 10.1007/s10439-018-2041-7

This is a first author paper of mine where, along with Dooyoung Lee and Dan Hammer, I studied how the relative densities of E-selectin and ICAM-1 affect the different steps of the leukocyte adhesion cascade. This cascade canonically consists of tethering, rolling, firm arrest, and transmigration. Using a recombinant protein surface, we could observe the first three steps in a highly controlled environment with specified densities. Thus, we could experimentally probe predictions made previously in the Hammer lab regarding synergy between selectins and adhesion molecules. In this case, we saw that optimal levels of firm arrest occurred on surfaces containing equimolar amounts of E-selectin and ICAM-1 or surfaces containing a 10X molar excess of ICAM-1. However, these surfaces required a certain level of ligand density (O(10^2) sites/µm^2), below which cells were unable to roll or arrest on the surface. Surfaces containing only one of the ligands were much less efficient at recruiting cells from the free stream compared to surfaces with both E-selectin and ICAM-1. Finally, we also showed almost no change in rolling velocity or time to stop on any of the surfaces, suggesting that the T cells control this aspect of the adhesion cascade independently of the adhesive surface.

Read this article on SpringerLink!

DOI: 10.1007/s12195-018-0519-x

This study is a continuation and extension of my previously published work with Dominguez and Hammer showing a similar phenomena of migration against the direction of fluid flow. However, instead of T lymphocytes, the cells in this manuscript are hematopoietic stem and progenitor cells, which are a more primitive immune cell type. These results show that possibly many immune cells show a similar behavior, which increases the likelihood that this behavior is serving an important biological purpose.

Read about it on the JCS website.

Published in: Integrative Biology (2015)

This study shows that activated T cells use the direction of flow and the identity of the adhesive ligand to determine in which direction the cell should migrate. On VCAM-1-functionalized surfaces, T cells migrate with the direction of flow, while they migrate upstream on ICAM-1-functionalized surfaces. In addition, we showed that this directionality is mediated by the beta-2 integrin of LFA-1.

Read the abstract on PubMed.