NECTIN-4-redirected T cell Antigen Coupler T cells bearing CD28 show superior antitumor responses against solid tumors

Front Immunol. 2024 Dec 13:15:1456443. doi: 10.3389/fimmu.2024.1456443. eCollection 2024.

Abstract

Introduction: T cell Antigen Coupler (TAC) T cells harness all signaling subunits of endogenous T cell receptor (TCR) to trigger T-cell activation and tumor cell lysis, with minimal release of cytokines. Some of the major obstacles to cellular immunotherapy in solid tumors include inefficient cell infiltration into tumors, lack of prolonged cellular persistence, and therapy-associated toxicity.

Methods: To boost the cytotoxic potential of TAC-T cells against solid tumors, we generated a novel NECTIN-4-targeted TAC-T variant, NECTIN-4 TAC28-T, which integrated the co-stimulatory CD28 cytoplasmic region, and compared the anti-tumor activities between NECTIN-4 TAC-T cells and NECTIN-4 TAC28-T cells in vitro and vivo.

Results: We demonstrated NECTIN-4 TAC28-Tcells could be effectively activated by NECTIN-4 protein-coated magnetic beads (NECTIN-4-beads), and further revealed that the incorporated CD28 co-stimulatory domain enhanced their activation and proliferation capabilities. Notably, NECTIN-4 TAC28-T cells exhibited better anti-tumor effects both in vitro and in vivo than the original NECTIN-4 TAC-T cells.

Discussion: Our data highlighted that NECTIN-4 TAC28-T cells may represent a promising, safe and effective cell therapy for NECTIN-4-overexpressing solid tumors.

Keywords: CD28; NECTIN-4; T cell Antigen Coupler (TAC-T); adoptive cell transfer therapy; solid tumor.

MeSH terms

  • Animals
  • CD28 Antigens* / immunology
  • CD28 Antigens* / metabolism
  • Cell Adhesion Molecules* / immunology
  • Cell Adhesion Molecules* / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods
  • Lymphocyte Activation / immunology
  • Mice
  • Nectins
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • CD28 Antigens
  • NECTIN4 protein, human
  • Cell Adhesion Molecules
  • Receptors, Antigen, T-Cell
  • Nectins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was partially supported by Guangdong Provincial Natural Science Foundation (2019A1515110831), Wenzhou Municipal Science and Technology Research Program (2018ZY001), Shandong Provincial Key R & D programs (2021CXGC011102), Construction Fund of Key Medical Disciplines of Hangzhou, Basic Public Welfare Research Program of Zhejiang Province (LQ21C080002), and Pioneer and Leading Goose R&D Program of Zhejiang (2024C03163).