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 8

Bona fide IK are more abundant in malignant areas of human GBMs.

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Bona fide IK are more abundant in malignant areas of human GBMs. (A) Thr...
(A) Three-dimensional rendering of a confocal scanning of the tissue block biopsy containing T cells. Higher magnification of the reconstructed transparency shows a representative CD3+ T cell with kinaptic morphology (green). Zenithal view of the kinaptic T cell reveals the characteristic triangular shape with a clear leading lamellipodium (arrow) and TCR/CD3-rich uropod (arrowhead). The visualization of the GFAP+ adjacent tumor cells (magenta) and DAPI+ nuclei (blue) revealed close apposition with malignant cells. Zoom-in image of the transparency-based reconstruction displays the shape and details of the CD3 distribution. Magnification, 2×. An illustration depicting the interpretation of the T cell shape is also shown. (B) Confocal transparency projection shows the distribution of CD3 with higher fluorescence intensity at the trailing uropod. Fluorescence intensity scale (FI-CD3) evidences the uropod highly fluorescent. (C) Measurement of the relative fluorescence of CD3 along the yellow broken line revealed a scarce increase of fluorescence at the front lamellipodium (arrow 1) but a high increase at the uropod (arrow 2). (D) Three-dimensional isosurface rendering of kinaptic cell distinguishing the areas with low and high CD3 intensity and nucleus. Zenithal view, slight rotation of the x axis, and slight rotation of the z axis are shown. Scale bar: 2 μm. (E) Central optical plane of the T cell kinapse shows the orientation of the nuclear indentation toward the uropod, suggesting the direction of the motile T cell (blue arrow). A diagram for interpretation is also shown. (F) Examples of T cells with either regular rounded or triangular shape, and the latter with a high fluorescent CD3+ uropod. On the outline, red circles limit the leading front, and green circle indicates the CD3-rich uropod of the kinaptic T cell. Graphs show the quantification of percentages of T cells with triangular shape and with bona fide IK. ***P < 0.001 and ****P < 0.0001, Student t test and Mann-Whitney U test. (G) Illustrative diagram of the shape of a human T cell kinapse in a malignant area.