Infiltrating CTLs in Human Glioblastoma Establish Immunological Synapses with Tumorigenic Cells

Abstract

The immunological synapse between T cells and tumor cells is believed to be important for effective tumor clearance. However, the immunological synapse has never been imaged or analyzed in detail in human tissue. In this work, intercellular interactions between T cells and tumor cells were analyzed in detail in human glioblastoma. After characterization of the population of infiltrating T cells by multiple immunofluorescence staining and stereological quantification, the microanatomy of T cell-tumor cell intercellular communication was analyzed in detail using confocal microscopy and three-dimensional rendering. Cytotoxic T lymphocytes that infiltrated human glioblastoma underwent rearrangement when in contact with tumor cells, to form a three-dimensional structure in the intercellular contact area

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

“…Most notably, enhancing tumor infiltrating cytotoxic T cells has been strongly correlated with improved clinical outcome [34,49,50]. Importantly, these novel experimental treatment paradigms are frequently implemented without excluding patients having already undergone current (A, C) Control mice (n=5 mice) display significantly greater disorganization of tight junction proteins within the tumor area and at the tumor border and larger microvessel diameter than aflibercept-treated mice (n=4 mice) at both the tumor core and the tumor edge.…”

“…Immune cell infiltration of human GBM is extensive, with monocytes/macrophages representing the largest cellular fraction and growing evidence of CD8+ T cell involvement [33,34]. Both CD8+ and CD4+ T-cell responses have been shown to drive VEGF upregulation in the CNS under neuroinflammatory conditions, which could contribute to angiogenesis and tumor progression [35,36].…”

“…Both CD8+ and CD4+ T-cell responses have been shown to drive VEGF upregulation in the CNS under neuroinflammatory conditions, which could contribute to angiogenesis and tumor progression [35,36]. Alternatively, tumor antigen-specific cytotoxic CD8+ T cells and T helper 1/17 CD4+ T cells have been shown to contribute to antitumor immunity, hindering tumor outgrowth [34,[37][38][39]. Clinical trials are currently underway combining antiangiogenic and immune-based therapies, including a phase II trial by the Alliance for Clinical Trials in Oncology (clinicaltrials.gov identifier NCT01814813) comparing the efficacy of bevacizumab with and without a heat shock protein-peptide complex (HSPPC-96) vaccine.…”

Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell function in vivo

“…Thus, the function of stable IS induced by higher antigen levels may be related more closely to perforin-mediated cytotoxicity (20) and/or cytokine secretion (15,22). In addition to these in vitro studies, we and others have described SMACs in T cells in vivo, and the resulting cellular reorganization in "postsynaptic" target cells during the effector phase of an antiviral immune response (14-16, 25, 24) and in human brain tumors (17). Thus, although IS appear relevant to viral clearing and cytotoxicity in vitro and in vivo (14-17, 23, 24), their absolute requirement has been questioned (19)(20)(21)25).…”

“…According to Monks et al (1) and subsequently supported by many studies (2)(3)(4)(5)(6)(7)(8)(9), upon ligation of the MHC/peptide complex by the T-cell receptor (TCR), several membrane-associated proteins, including the TCR complex and downstream kinases, become concentrated at the center of the contact interface, the central supramolecular activation complex (cSMAC), whereas others [e.g., lymphocyte function-associated antigen 1 (LFA-1), talin, and CD45] are excluded to form an outer concentric ring, the peripheral supramolecular activation complex (pSMAC) (1,5,10,11). The structures displayed by CD8 + cytotoxic T lymphocytes (CTL) as they interact with target cells share several important morphological and functional characteristics with the CD4/APC interaction (5,(12)(13)(14)(15)(16)(17)(18). Stinchcombe et al (12) examined the synapses between primary mouse CD8 + CTL and mouse mastocytoma targets, describing in detail the formation of cSMAC and pSMAC at the cytotoxic interface and how cytolytic granules are brought to a secretory subdomain within the cSMAC to focus cytotoxicity onto the targets (5,12,13).…”