Promising Small Molecule Candidate for Hematological Malignancy and GVHD

Oncotarget published "CrkL is required for donor T cell migration to GvHD target organs" which reported that the success of cancer therapies based on allogeneic hematopoietic stem cell transplant relies on the ability to separate graft-versus-host disease from graft-versus-tumor responses. In vitro, CrkL-deficient T cells fail to polymerize actin in response to the integrin ligand ICAM-1, resulting in defective migration. In line with this, these authors found that although CrkL-deficient T cells could clear hematopoietic tumors, they failed to clear the same tumor growing subcutaneously, highlighting the role of CrkL in controlling T cell migration into peripheral tissues. Dr. Mobin Karimi from The SUNY Upstate Medical University said, "T cell migration out of the vasculature into peripheral tissue is a key control point in the inflammatory response." Although trafficking to tissues is required for protective immunity, uncontrolled T cell infiltration into tissue can result in exacerbated inflammation and tissue damage. T cell recruitment is highly regulated by the local endothelial cells which, in response to pro-inflammatory cues, up-regulate molecules such as chemokines and adhesion receptors. These molecules promote T cell adhesion to the endothelial monolayer, and guide migration through the monolayer into the tissue. Activated T cells lacking Crk proteins fail to polymerize actin downstream of LFA-1, and migrate slower and less directionally than their WT counterparts. Importantly, these mutant T cells also have defects in crossing endothelial monolayers in vitro, and they fail to traffic to sites of inflammation in vivo. Additionally, using a clinically relevant mouse model of graft-versus-host disease/graft-versus-leukemia, these authors showed that T cells lacking Crk proteins can efficiently clear tumor cells but cause little-to-no GvHD pathology. The Crk proteins are widely expressed across tissues and have many biological functions, all of which stem from their role as adaptor proteins that coordinate signaling complexes downstream of cell surface receptors. Crk proteins are particularly important for adhesion and migration. They have been shown to localize to adhesion sites and regulate the stability of these structures in non-hematopoietic cells, and alterations in their expression are associated with invasive potential in several tumors. The Karimi Research Team concluded in their Oncotarget Research Output, "Going forward, it will be interesting to identify CrkL binding partners and other signaling molecules needed for integrin-dependent actin responses and passage into inflamed tissues. Targeting these molecules could be used to more finely control T cell trafficking in the treatment of inflammatory diseases and for the design of next-generation adoptive T cell therapies." Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27509 DOI - https://doi.org/10.18632/oncotarget.27509 Full text - https://www.oncotarget.com/article/27509/text/ Correspondence to - Mobin Karimi - karimim@upstate.edu Keywords - graft-versus-host disease, CrkL, T cell, migration, inflammation About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Copyright © 2021 Impact Journals, LLC Impact Journals is a registered trademark of Impact Journals, LLC