Imbalance of immunological synapse-kinapse states reflects tumor escape to immunity in glioblastoma
Laura R. Díaz, … , Carlos Barcia Sr., Carlos Barcia Jr.
Laura R. Díaz, … , Carlos Barcia Sr., Carlos Barcia Jr.
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e120757. https://doi.org/10.1172/jci.insight.120757.
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Resource and Technical Advance Immunology

Imbalance of immunological synapse-kinapse states reflects tumor escape to immunity in glioblastoma

Abstract

Since the proper activation of T cells requires the physical interaction with target cells through the formation of immunological synapses (IS), an alteration at this level could be a reason why tumors escape the immune response. As part of their life cycle, it is thought that T cells alternate between a static phase, the IS, and a dynamic phase, the immunological kinapse (IK), depending on high or low antigen sensing. Our investigation performed in tissue samples of human glioma shows that T cells are able to establish synapsing interactions not only with glioma tumorigenic cells, but also with stromal myeloid cells. Particularly, the IS displaying a T cell receptor–rich (TCR-rich) central supramolecular activation cluster (cSMAC) is preferentially established with stromal cells, as opposed to malignant cells. Conversely, T cells in the malignant areas showed distinct morphometric parameters compared with nonneoplastic tissue — the former characterized by an elongated shape, well-suited to kinaptic dynamics. Importantly, high-resolution 3-dimensional analyses demonstrated the existence of bona-fide IK preferentially arranged in malignant areas of the tumor. This imbalance of IS/IK states between these 2 microenvironments reveals the low antigenic sensing of T cells when patrolling tumorigenic cells and reflects the immunoevasive environment of the tumor.

Authors

Laura R. Díaz, Elena Saavedra-López, Leire Romarate, Izaskun Mitxitorena, Paola V. Casanova, George P. Cribaro, José M. Gallego, Ana Pérez-Vallés, Jerónimo Forteza-Vila, Clara Alfaro-Cervello, José M. García-Verdugo, Carlos Barcia Sr., Carlos Barcia Jr.

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Figure 5

T cells form TCR/CD3 cSMAC at the T cell–GFAP+ cell interacting interface.

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T cells form TCR/CD3 cSMAC at the T cell–GFAP+ cell interacting interfac...
Three-dimensional confocal analyses of 2 representative examples of T cell cSMAC formation with GFAP-expressing cells within GBM tissue (synapse 1 [A, B, C, and D] and synapse 2 [E, F, G, and H]). (A and E) T cell, evidenced by CD3 (green), establishes a close apposition with a GFAP+ cell (red). Cell nuclei are counterstained with DAPI (blue). (B and F) At the level of the interface between the T cell and the APC illustrated in A and E, we visualized the intensity of CD3 fluorescence (FI-CD3), according to the fluorescence intensity scale, and we observed an increase in CD3 at the center of the interaction. A higher magnification of the white rectangle is shown. Asterisks indicate the location of the T cell. The CD3 intensity in the regular green channel represented was measured along the yellow broken arrow. The measurement of the intensity at this level is illustrated in graphs C and G. Arrows indicate the cSMAC high fluorescent areas. (D and H) Over gray-scale color, outlines of the 2 interacting cells are illustrated (green and red broken lines). Considering the planes 1 and 2 (yellow broken lines) illustrated, a 3-D reconstruction of the interacting cells (CD3/MHCII/DAPI) are shown in a longitudinal clipping plane (CP) and a CP at the interface to observe the CD3 cluster at the intercellular interaction. Scale bars: 5 μm.