Led by Prof. Tao Dong (CAMS Oxford Institute (COI) Co-Director & MRC Translational Immune Discovery Unit (TIDU) Principal Investigator), Prof. Michael Dustin (Kennedy Institute and COI Principal Investigator), Dr Megat Abd Hamid (COI) & Dr Pablo Cespedes (COI), researchers have discovered that tumour-specific T cells expressing the integrin CD103 can also express CD61, an integrin previously only well-documented in non-lymphocytic cells. They found that presence of CD61 at the synapse between T cells and antigen-presenting cells can modulate T cell receptor (TCR) signalling to improve anti-tumour cytotoxicity and promote control of tumour growth.
Integrins are large, heterodimeric transmembrane glycoproteins that facilitate adhesion between cells, and with the extracellular matrix. They require the pairing between an alpha-and beta-subunit to exit the endoplasmic reticulum and reach the cell surface to become functionally active. CD103, or integrin alpha-E, usually pairs with integrin beta-7 on human immune cells, but here they show that it pairs with CD61, or integrin beta-3, instead. This is the first evidence of CD61 expression on human cytotoxic T cells.
The interaction between CD103 and CD61 occurs in the central synapse point of interaction between the T cell and antigen-presenting cell. TCRs are also present in this area where they interact with peptide-MHC complexes for activation of the T cells. The researchers found that CD61 presence at the synapse increased TCR signalling and T cell activation which in turn led to better control of tumour growth in a mouse model.
In the tumour microenvironment, immune cells can be excluded from the area and those that are present generally display signs of cellular exhaustion which allows the tumour to continue growing unchecked. One major finding of this study was that the T cells expressing CD61 in concert with CD103 did not display signs of exhaustion and instead exhibited enriched PD-1 expression, a marker of T cell activation.
CD103 expression on T cells has previously been shown to be associated with improved outcomes in cancer patients. Previously, the Dong group has shown that CD103 expression increases antigen sensitivity, which enabled faster cancer recognition and rapid anti-tumor cytotoxicity. This new discovery suggests that these CD103+ CD61+ T cells may play an important role in targeted killing of cancer cells to reduce tumour growth, opening new avenues for future immunotherapy strategies.
This work comes at the end of a decade-long effort by the Dong group to create a pipeline for the discovery of novel interactions and protein expression in T cells in a bid to improve understanding of T cell functions in cancer & viral infection. This work shows that by taking a target discovery approach to understand differences in T cells, new avenues for research can be discovered, validated, and investigated. For this pipeline to become a reality, a highly collaborative effort was made across multiple COI Principal Investigators and colleagues including Prof. Roman Fischer (Target Discovery Institute (TDI) & COI), Dr Yanchun Peng (COI), Prof. Graham Ogg (TIDU & COI), Dr Ricardo Fernandes (COI), Dr Uzi Gileadi (TIDU), Dr Zhu Liang (COI), Professor Benedikt Kessler (TDI & COI), Prof. Najib Rahman (Respiratory Medicine & COI), Prof. Claire Verrill (Nuffield Department of Surgical Sciences & COI) and many more.
The full article can be found here.