TMEM123 (theoretical MW: 21.5 kDa) is a highly glycosylated mucin-like protein with a type 1 plasma membrane topology having 56 predicted glycosylation sites, in particular 47 O-linked (NetOGlyc 4.0), and 9 N-linked (NetNGlyc 1.0). Very little is known about the functional role of TMEM123. We demonstrated that it represents a novel important player in the CRC tumor microenvironment (TME), contributing to cancer immune surveillance. In this study, we investigated the TMEM123 protein (alias Porimin, KCT-3), a protein that emerged in our study of TILs in solid cancers. Studies focused on the characterization of TILs in CRC would allow to elucidate the molecular determinants associated with a positive outcome of this cancer. The infiltration of CD8+ T lymphocytes into CRC tumors, has been established globally as a significant predictor of patient prognosis ( 6, 7). TILs have been associated with lower recurrence and case fatality of CRC, independent of stage. Immune cells present in the tumor-microenvironment (TME) play an important role in modulating tumour growth, progression or elimination. Indeed, tumor-infiltrating lymphocytes (TILs) recruited to the tumor area witness the host’s immune response against cancer cells and have gained increasing attention as prognostic parameters in different cancers ( 4, 5).Ĭolorectal cancer (CRC) is a highly heterogeneous disease, with a diverse and plastic immune cell infiltrate. On the other side neoantigens generated during tumorigenesis could in principle be recognized as foreign and rejected by specific effector T lymphocytes that traffic to the tumor site, where CD8+ T cells mediate direct killing of tumor cells ( 3). Cancer cells can actively corrupt their microenvironment by releasing a number of paracrine growth factors, cytokines and metabolites that perturbate signaling and metabolism of surrounding stroma, and mask cancer cells from the immune system to prevent their destruction ( 2). Multiple immune-suppressive mechanisms are triggered by the interplay between malignant cells and the surrounding tissue. The crosstalk between cancer cells and the immune system has gained much attention in recent years ( 1). We propose an active role for TMEM123 in the anti-cancer activity of T cells within tumour microenvironment. Using tumoroid-lymphocyte co-culture assays, we found that lymphocytes form clusters through TMEM123, anchoring to cancer cells and contributing to their killing. TMEM123 silencing modulates the underlying signaling pathways dependent on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, which are required for synaptic force exertion. TMEM123 localizes in the protrusions of infiltrating T cells, it contributes to lymphocyte migration and cytoskeleton organization. The presence of infiltrating TMEM123+ CD8+ T cells is associated with better overall and metastasis-free survival. We discovered that the protein TMEM123 is over-expressed in tumour-infiltrating CD4 and CD8 T lymphocytes and it contributes to their effector phenotype. In the tumor site, the interplay between effector immune cells and cancer cells determines the balance between tumor elimination or outgrowth. 9Anatomic Pathology Unit, Humanitas University Research Hospital, Milan, ItalyĬolorectal cancer (CRC) is a leading cause of cancer-associated death.8Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.7Department of Biosciences, Università degli Studi di Milano, Milan, Italy.6Department of Oncology and Hemato-oncology, Università degli Studi di Milano, Milan, Italy.5Department of Surgery, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.4Department of Pathology, European Institute of Oncology, Milan, Italy.2Institute of Pathology, University Hospital Basel, Basel, Switzerland.1Istituto Nazionale Genetica Molecolare (INGM), Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.Terracciano 9* and Renata Grifantini 1,3* Sarnicola 1, Elisa Cassinotti 5, Ludovica Baldari 5, Giuseppe Viale 4,6, Stefano Biffo 1,7, Sergio Abrignani 1,8, Luigi M. Elisa Pesce 1*†, Chiara Cordiglieri 1†, Mauro Bombaci 1, Serenella Eppenberger-Castori 2, Stefania Oliveto 1, Cristina Manara 1, Mariacristina Crosti 1, Caner Ercan 2, Mairene Coto 2, Andrea Gobbini 1, Susanna Campagnoli 3, Tiziano Donnarumma 3, Manuele Martinelli 3, Valeria Bevilacqua 1, Elisa De Camilli 4, Paola Gruarin 1, Maria L.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |