Exploiting T cell signaling to optimize engineered T cell therapies

T cell antigen receptor (TCR) and chimeric antigen receptor (CAR) have similar but different signaling mechanisms, leading to distinct clinical outcomes of TCR-T and CAR-T therapies. Naturally evolved TCR contains sophisticated regulatory elements that can be incorporated into CAR to improve performance. Tuning the strength of TCR/CAR signaling in a context-dependent manner enhances antitumor function and long-term persistence of engineered T cells. Engineered T cell therapies, mainly chimeric antigen receptor (CAR)-T and T cell receptor (TCR)-T, have become the new frontier of cancer treatment. CAR-T and TCR-T therapies differ in many aspects, including cell persistence and toxicity, leading to different therapeutic outcomes. Both TCR and CAR recognize antigens and trigger T cell mediated antitumor response, but they have distinct molecular structures and signaling properties. TCR represents one of the most complex receptors, while CAR is a single-chain chimera integrating modules from multiple immune receptors. Understanding the mechanisms underlying the strengths and limitations of both systems can pave the way for the development of next-generation T cell therapy. This review synthesizes recent findings on TCR and CAR signaling and highlights the potential strategies of T cell engineering by signaling refinement. Engineered T cell therapies, mainly chimeric antigen receptor (CAR)-T and T cell receptor (TCR)-T, have become the new frontier of cancer treatment. CAR-T and TCR-T therapies differ in many aspects, including cell persistence and toxicity, leading to different therapeutic outcomes. Both TCR and CAR recognize antigens and trigger T cell mediated antitumor response, but they have distinct molecular structures and signaling properties. TCR represents one of the most complex receptors, while CAR is a single-chain chimera integrating modules from multiple immune receptors. Understanding the mechanisms underlying the strengths and limitations of both systems can pave the way for the development of next-generation T cell therapy. This review synthesizes recent findings on TCR and CAR signaling and highlights the potential strategies of T cell engineering by signaling refinement. presentation of intracellular protein antigen occurs in most nucleated cells, including tumor cells. The proteasome degrades intracellular proteins in the cytoplasm to generate linear peptide fragments, which are then transported into the endoplasmic reticulum (ER) via a transporter associated with antigen presentation and loaded onto an MHC molecule. The loaded peptide/MHC (pMHC) complexes are then exported to the cell surface, recognized by distinct TCRs. However, tumor cells often downregulate MHC expression to escape immune surveillance. when TCR recognizes its antigen presented on the target cells (e.g., tumor cells), the T cell and its target cell form a tight conjugation. An IS, with its typical bull’s-eye structure, is formed at the interface between these two cells. The IS consists of TCR, coreceptors, co-stimulatory-receptors, integrin, and other transmembrane proteins. The formation of IS plays an important role in TCR signal initiation and maintenance. Compared to TCR, CAR engagement forms a non-typical and disorganized IS. during T cell activation, T cells differentiate into different types of effector cells with distinct functions. CD8+ T cells differentiate to cytotoxic T lymphocytes (CTLs) with killing functions. CD4+ T cells differentiate to helper T cell subtypes that secrets signature cytokines such as Th1, Th2, and Th17. In general, CTL, Th1, and Th2 are considered to have antitumor functions, while the roles of Th17 in tumors are context-dependent. the tumor microenvironment has complicated immune suppression mechanisms to induce T cell dysfunction, featured with downregulation of proliferation potential and effector functions and upregulations of immune checkpoints such as PD-1 and CTLA-4. Moreover, exhausted T cells have distinct epigenetic states that make them difficult to be fully reinvigorated. in patients, the long-term survival and proliferation potential of infused T cells is determined by the population of memory T cells in the product. Memory T cells are heterogeneous and they follow the differentiation trajectory that gradually acquires effector functions in the compensation of proliferation potential. These memory subtypes along the path are stem-like central memory T cells (Tscm), central memory T cells (Tcm), and effector memory T cells (Tem). Tscm cells show the best persistence in patients with CAR-T therapy. CAR-T cell persistence in vivo significantly correlates with its efficacy.