About this Research Topic

Background

T cell receptor (TCR) and B cell receptor (BCR) stimulation by antigen on the surface of an antigen-presenting cell (APC) induces the formation of the immunological synapse (IS). The IS is a specialized cell-cell interface contact area that consists of a signalling platform for integration of signals leading to intercellular communication, in order to ensure efficient TCR and BCR signal transduction, T and B cell activation and the proper execution of diverse lymphocyte effector functions. Included among these, IS formation triggers the convergence of T and B lymphocyte secretory vesicles, including multivesicular bodies (MVB) and other lysosome-related organelles (LRO), towards the microtubule-organizing center (MTOC) and the polarization of MTOC and these vesicles to the IS. These traffic events lead to LRO degranulation at the synaptic cleft. LRO content secreted at the IS has an important role on cytotoxic T lymphocyte (CTL)—mediated cytotoxicity and antigen extraction at the B lymphocyte synapse.



Goal

T-cell redirecting approaches to selectively eliminate tumor cells are useful strategies for cancer immunotherapy and are based in the formation of T cell-target cell conjugates, although these approaches have poor therapeutic results against solid tumors. These approaches include strategies to conjugate T lymphocytes with cancer cells using chimeric antigen receptors (CAR) or bispecific antibodies recognizing cell-surface tumor-associated antigens. Despite the fact that these strategies render functional IS in terms of signalling leadin to LRO secretory polarized traffic and tumor cell death, the spatiotemporal architecture of the IS formed under these redirecting strategies is different to that found in canonical synapses.

The topology and dynamics of the IS developed in response to the redirecting approaches is poorly understood in comparison to the canonical IS and appears to limit IS efficiency and effector cell activation and life span. Canonical IS-tuned CAR signalling enhances anti-tumor activity of CAR T cells and T-cell engaging bispecific antibodies, and recent evidence shows that IS quality measurements correlate with patient clinical outcomes. Thus, basic research on IS structure and signalling as well as studies regarding the way that the IS quality might predict the efficiency of diverse T-cell redirecting strategies, the contribution of endogenous TCR to IS quality and how to define strategies to improve T-cell redirecting approaches based on IS quality and more efficient TCR/BCR/CAR/specific antibody-elicited signalling, are themes that will be welcome under this topic.



Scope and information for authors

Th IS developed by redirecting approaches can be tuned to exhibit amplified synaptic strength, enhanced IS size and duration, abundance of secreted cytokines, prolonged T cell life span and enhanced killing of tumor cells, including solid tumors. Due to the fact that the IS is a vital component during the T cell response, which largely determines the clinical outcomes of several T-cell based therapies, the goal of this topic is to predict and facilitate the development of therapeutic interventions based on immune cell redirecting strategies to more precisely modulate and control the compromised immune response during tumor growth.

Potential specific topics include, but are not limited to:

- Structural and functional studies on canonic and redirecting immune synapses.

- Studies on synaptic architecture.

- Signal transduction during IS-derived responses.

- Studies on secretory polarized traffic towards the IS.

- Bispecific antibody-based T cell redirecting strategies.

- CAR T cell-based T cell redirecting strategies.

- Image tools, including artificial intelligence image analysis, to study IS structure and function.

Keywords: Immunological synapse, T lymphocytes, B lymphocytes, CAR T cells, Polarized Secretory Traffic, Lysosome related organelles, Actin cytoskeleton, Cancer Immunotherapy

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