Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion

Harrer DC, Schlierkamp-Voosen T, Barden M, Pan H, Xydia M, Herr W, Dörrie J, Schaft N, Abken H (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Cells MDPI

Book Volume: 14

Article Number: 901

Journal Issue: 12

DOI: 10.3390/cells14120901

Abstract

T cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response. To extend T cell cytotoxic capacities, we engineered CAR T cells to constitutively release an immunostimulatory variant of soluble SLAMF6. While wild-type SLAMF6 induces T cell exhaustion, CAR T cells with the soluble Δ17-65 SLAMF6 variant exhibited refined, CAR redirected functionality compared to canonical CAR T cells. CD28-ζ CAR T cells releasing soluble SLAMF6 increased IFN-γ secretion and augmented CD25 upregulation on CD4+ CAR T cells upon CAR engagement by pancreatic carcinoma and melanoma cells. Moreover, under conditions of repetitive antigen encounter, SLAMF6-secreting CAR T cells evinced superior cytotoxic capacity in the long term. Mechanistically, SLAMF6-secreting CAR T cells showed predominantly a central memory phenotype, a PD-1- TIGIT- double negative profile, and reduced expression of exhaustion-related transcription factors IRF-4 and TOX with augmented amplification and persistence capacities. Overall, CAR T cells engineered with the release isoform 2 SLAMF6 establish an auto-stimulatory loop with the potential to boost the cytolytic attack against solid tumors.

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Universität Regensburg DE Germany (DE) Bayerisches Zentrum für Krebsforschung (BZKF) DE Germany (DE)

How to cite

APA:

Harrer, D.C., Schlierkamp-Voosen, T., Barden, M., Pan, H., Xydia, M., Herr, W.,... Abken, H. (2025). Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion. Cells, 14(12). https://doi.org/10.3390/cells14120901

MLA:

Harrer, Dennis Christoph, et al. "Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion." Cells 14.12 (2025).

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