| Autor: |
Lu J; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.; Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China., Veler A; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK., Simonetti B; School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK., Raj T; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK., Chou PH; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK., Cross SJ; Wolfson Bioimaging Facility, University of Bristol, Bristol BS8 1TD, UK., Phillips AM; Department of Electrical Engineering & Electronics and Computational Biology Facility, University of Liverpool, Liverpool L69 7ZX, UK., Ruan X; Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA., Huynh L; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK., Dowsey AW; Bristol Veterinary School, University of Bristol, Bristol BS40 5DU, UK., Ye D; Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.; Shanghai Genitourinary Cancer Institute, Shanghai 200032, China., Murphy RF; Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.; Department of Biological Sciences, Biomedical Engineering and Machine Learning, Carnegie Mellon University, Pittsburgh, PA 15213, USA., Verkade P; School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK., Cullen PJ; School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK., Wülfing C; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK. |
| Abstrakt: |
T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct, with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation. |
