Adenosine regulates CD8+ T cell activation by disrupting the ARP2/3 and Cofilin pathway could prevent immunological synapse formation and motility
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Abstract
Immunosurveillance is a powerful defines mechanism by which both innate and adaptive arms of the immune system mediate to protect from tumour development. The tumour microenvironment (TME) plays a crucial role in regulation of CD8+ cytotoxic T lymphocytes (CTLs) and suppresses their function. When these CTLs migrate from tumour-draining lymph nodes (TDLN) into the tumour to form tumour-infiltrating lymphocytes (TIL) they quickly lose their CTL function. Tumour growth is associated with the frequent production of immunosuppressive molecules within the tumour microenvironment that inhibit anti-tumour CTL effector function resulting in the secretion of tumour progression molecules. Immunotherapies that block immune inhibitory receptors have developed the treatment strategy for advanced-stage tumours. Here, we review this study to improve the effector function of CD8+ T cells following adoptive transfer to eliminate tumour cells by validating a selected set of proteins that are significantly changed in their levels of expression through proteomic analysis obtained from a tandem mass tagging (TMT) comparison of the whole proteome of purified populations of CL4 CD8+ T cells isolated from TDLNs with those that form TILs in RencaHA tumour-bearing mice. To conduct these experiments in vitro and vivo, a highly characterized murine Renal carcinoma (Renca) model was used. Renca cells were transfected with a plasmid construct containing the HA protein from influenza virus A/PR/8 H1N1 as a cell surface neo-tumour-specific antigen and Thy1.1+, KdHA-specific, CL4 TcR transgenic CD8.
As a result, we demonstrated that in vivo ARP2/3 was significantly decreased (>10 fold) in TILs compared to TDLNs. Moreover, we also showed that when in vitro activated CL4 cells were exposed to adenosine, which plays a crucial role in modulating both the ARP2/3 Complex and Cofilin proteins, ARP2/3 levels decreased (>1.5 fold) compared to untreated CL4 cells, resulting in possible prevention of, for example, the formation of the immunological synapse. Adenosine treatment, however, led to increased levels of Cofilin.
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