Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation

Abstract

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.

Keywords: T cell-based immunotherapy; bispecific antibody; chimeric antigen receptor; immunological synapse; metabolism.

Figure 1

Natural IS formation in cytotoxicity T lymphocyte. After recognition of tumor cell, TCR-CD3 complexes aggregate and form TCR microclusters (TCR-MCs). TCR-MCs contain various TCR downstream signaling molecules and adhesion molecules. These TCR-MCs move toward the center of the interface between T cell and its target and form the central supramolecular activation cluster (cSMAC). In this process, adhesion molecule LFA-1 dissociates from TCR-MCs and remains in the peripheral region of the IS, forming the peripheral SMAC (pSMAC). The outmost ring of immune synapse is distal SMAC (dSMAC).

Figure 2

Structures of signaling transduction triggered by TCR, CAR, and bsAb. (A) In natural T cell, tumor antigen peptide is presented by APC and recognized by TCR. The associated CD3 molecule in TCR-CD3 complex will provide Signal 1 to T cell. The costimulatory signal (Signal 2) is provided by costimulatory molecules, such as CD28, 4-1 BB, etc. (B) In CAR-T cell, target antigens are directly recognized by CAR molecule’s scFv. Signal 1 and Signal 2 are provided by CD3ζ and costimulatory domain relatively in CAR’s intracellular domain. (C) In bsAb-T cell, bsAbs simultaneously recognize tumor antigen and CD3ϵ chain, and form a bridge between tumor cell and T cell. Similar to natural T cell, Signal 1 is still provided by TCR-CD3 complex. However, Signal 2 is lack in bsAb-mediated activation.

Figure 3

The formation of IS mediated by CAR and bsAb. (A) The structure of CAR-IS. The microclusters of CAR are dispersed in a multipolar manner surrounded by disorganized LFA-1 without a clear boundary of pSMAC. (B) The structure of bsAb-IS. Similar to TCR-IS, BsAb-IS has a conventional mature IS structure, with organized cSMAC, and a LAF-1 ring and actin accumulation at the periphery.

Figure 4

A summary of current strategies for obtaining enhanced efficacy and prolonged persistence from redirected T cells. (A) The improvement of IS stability. (B) The adjustment of IS-mediated signaling. (C) The switch of T-cell metabolism toward memory phenotype.