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Similarities and Differences between Chimeric Antigen Receptor and T Cell Receptor Signaling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (1 August 2022) | Viewed by 19885

Special Issue Editor

Dr. Loredana Saveanu

E-Mail Website
Guest Editor
INSERM U1149, Center for Research on Inflammation, Bichat Medical School, 75018 Paris, France
Interests: antigen presentation; TLR signaling; TCR signaling; endosomal trafficking

Special Issue Information

Dear Colleagues,

T cell-based immunotherapy has revolutionized the treatment of malignant B hemopathies, and its future advances could lead to effects on solid cancers. Its optimization requires a deep knowledge of the molecular mechanisms that regulate the signaling of engineered antigen T cell receptors, which are either synthetic antigen T cell receptors (TCRs) or chimeric antigen receptors (CARs). The mechanisms that control the signaling of synthetic TCRs are similar to those of endogenous TCR and are thus better understood than the mechanism controlling the signaling and trafficking of CARs. However, several recent studies have highlighted the similarities and differences between the signaling of these two types of receptors. In addition, we are going through a period of fascinating discoveries in the field of CAR signaling, learning that costimulatory domain, the transmembrane region or the length of the linkers have a major impact on CAR efficiency, probably by changing the trafficking and signaling of the receptor.

We are pleased to invite you to participate in this Special Issue that will improve our understanding of molecular mechanisms that govern TCR and various CARs trafficking and signaling. This Special Issue includes original experimental data, literature reviews, and comments on recent developments in the field. 

Dr. Loredana Saveanu
Guest Editor

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Keywords

  • TCR
  • CAR
  • signaling
  • trafficking
  • immunotherapy
  • endosome
  • immune synapse
  • cytotoxicity

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Published Papers (3 papers)

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Research

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15 pages, 4412 KiB  
Article
The Effects of Chimeric Antigen Receptor (CAR) Hinge Domain Post-Translational Modifications on CAR-T Cell Activity
by Sachiko Hirobe, Keisuke Imaeda, Masashi Tachibana and Naoki Okada
Int. J. Mol. Sci. 2022, 23(7), 4056; https://doi.org/10.3390/ijms23074056 - 6 Apr 2022
Cited by 11 | Viewed by 3518
Abstract
To improve the efficacy and safety of chimeric antigen receptor (CAR)-expressing T cell therapeutics through enhanced CAR design, we analysed CAR structural factors that affect CAR-T cell function. We studied the effects of disulphide bonding at cysteine residues and glycosylation in the HD [...] Read more.
To improve the efficacy and safety of chimeric antigen receptor (CAR)-expressing T cell therapeutics through enhanced CAR design, we analysed CAR structural factors that affect CAR-T cell function. We studied the effects of disulphide bonding at cysteine residues and glycosylation in the HD on CAR-T function. We used first-generation CAR[V/28/28/3z] and CAR[V/8a/8a/3z], consisting of a mouse vascular endothelial growth factor receptor 2 (VEGFR2)-specific single-chain variable fragment tandemly linked to CD28- or CD8α-derived HD, transmembrane domain (TMD) and a CD3ζ-derived signal transduction domain (STD). We constructed structural variants by substituting cysteine with alanine and asparagine (putative N-linked glycosylation sites) with aspartate. CAR[V/28/28/3z] and CAR[V/8a/8a/3z] formed homodimers, the former through a single HD cysteine residue and the latter through the more TMD-proximal of the two cysteine residues. The absence of disulphide bonds did not affect membrane CAR expression but reduced antigen-specific cytokine production and cytotoxic activity. CAR[V/28/28/3z] and CAR[V/8a/8a/3z] harboured one N-linked glycosylation site, and CAR[V/8a/8a/3z] underwent considerable O-linked glycosylation at an unknown site. Thus, N-linked glycosylation of CAR[V/28/28/3z] promotes stable membrane CAR expression, while having no effect on the expression or CAR-T cell activity of CAR[V/8a/8a/3z]. Our findings demonstrate that post-translational modifications of the CAR HD influence CAR-T cell activity, establishing a basis for future CAR design. Full article
(This article belongs to the Special Issue Similarities and Differences between Chimeric Antigen Receptor and T Cell Receptor Signaling)
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Review

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24 pages, 984 KiB  
Review
Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”
by Karin Teppert, Xueting Wang, Kathleen Anders, César Evaristo, Dominik Lock and Annette Künkele
Int. J. Mol. Sci. 2022, 23(23), 14563; https://doi.org/10.3390/ijms232314563 - 23 Nov 2022
Cited by 9 | Viewed by 11513
Abstract
T cell-based immunotherapy has demonstrated great therapeutic potential in recent decades, on the one hand, by using tumor-infiltrating lymphocytes (TILs) and, on the other hand, by engineering T cells to obtain anti-tumor specificities through the introduction of either engineered T cell receptors (TCRs) [...] Read more.
T cell-based immunotherapy has demonstrated great therapeutic potential in recent decades, on the one hand, by using tumor-infiltrating lymphocytes (TILs) and, on the other hand, by engineering T cells to obtain anti-tumor specificities through the introduction of either engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs). Given the distinct design of both receptors and the type of antigen that is encountered, the requirements for proper antigen engagement and downstream signal transduction by TCRs and CARs differ. Synapse formation and signal transduction of CAR T cells, despite further refinement of CAR T cell designs, still do not fully recapitulate that of TCR T cells and might limit CAR T cell persistence and functionality. Thus, deep knowledge about the molecular differences in CAR and TCR T cell signaling would greatly advance the further optimization of CAR designs and elucidate under which circumstances a combination of both receptors would improve the functionality of T cells for cancer treatment. Herein, we provide a comprehensive review about similarities and differences by directly comparing the architecture, synapse formation and signaling of TCRs and CARs, highlighting the knowns and unknowns. In the second part of the review, we discuss the current status of combining CAR and TCR technologies, encouraging a change in perspective from “TCR versus CAR” to “TCR and CAR”. Full article
(This article belongs to the Special Issue Similarities and Differences between Chimeric Antigen Receptor and T Cell Receptor Signaling)
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22 pages, 1563 KiB  
Review
Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs)
by Chiara Cassioli, Laura Patrussi, Salvatore Valitutti and Cosima T. Baldari
Int. J. Mol. Sci. 2022, 23(22), 14255; https://doi.org/10.3390/ijms232214255 - 17 Nov 2022
Cited by 11 | Viewed by 4052
Abstract
Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially [...] Read more.
Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response. Full article
(This article belongs to the Special Issue Similarities and Differences between Chimeric Antigen Receptor and T Cell Receptor Signaling)
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