CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects
Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4<sup>+</sup> T cells. Here, we demonstrate that CD4<sup>+</sup> but not CD8<sup>+</sup> anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4<sup>+</sup> T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8<sup>+</sup> T cells in vivo. Tumor-infiltrating CD4<sup>+</sup> T28zT2 T cells are enriched with TCF-1<sup>+</sup>IL7R<sup>+</sup> memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4<sup>+</sup> T28zT2 T cells and CD8<sup>+</sup> anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4<sup>+</sup> T cells is a promising strategy for eradicating solid tumors.
Authors
- Robert Weinkove (ORCID: https://orcid.org/0000-0003-3645-7988)
- Shouheng Lin (ORCID: https://orcid.org/0000-0002-6248-5926)
- Yuekun Qi (ORCID: https://orcid.org/0000-0003-4431-3060)
- Georgia Carson
- Yongfang Zheng (ORCID: https://orcid.org/0000-0002-6650-0599)
- Bingjia He
- Bin-Chao Wang
- Jean Paul Thiery (ORCID: https://orcid.org/0000-0003-0478-5020)
- Ming O. Li
- Le Qin
- Dajiang Qin (ORCID: https://orcid.org/0009-0008-2792-3514)
- Zhaoyang Tang (ORCID: https://orcid.org/0000-0002-4798-2369)
- James Y. Lau (ORCID: https://orcid.org/0000-0003-0122-4068)
- Diwei Zheng (ORCID: https://orcid.org/0000-0001-8888-9630)
- Yao Yao (ORCID: https://orcid.org/0000-0002-5809-2740)
- Peng Li (ORCID: https://orcid.org/0000-0003-4530-2400)
- Yi-Long Lung Cancer Wu (ORCID: https://orcid.org/0000-0002-3611-0258)
- Kailin Xu (ORCID: https://orcid.org/0000-0003-1375-1084)
- Zhenfeng Zhang (ORCID: https://orcid.org/0000-0001-5621-9755)
- Bin Pan (ORCID: https://orcid.org/0000-0002-2606-2184)
- Jiang Lv (ORCID: https://orcid.org/0000-0001-6064-3882)
- Nathalie Wong (ORCID: https://orcid.org/0000-0003-2397-9189)
- M. Che
Institutions
- Xuzhou Medical College (CN)
- Chinese University of Hong Kong (HK)
- Malaghan Institute of Medical Research (NZ)
- Guangdong General Hospital (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Guangdong Academy of Medical Sciences (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102020
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.18