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Updated: Jun 10, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression
Seung Hun Shin1, Young Eun Lee2, Han-Na Yoon3
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Abstract:
The dysfunction of natural killer (NK) cells, mediated by transforming growth factor β1 (TGFβ1) within the tumor microenvironment, impedes antitumor therapy and contributes to poor clinical outcomes. Our study introduces self-activating chimeric antigen receptor (CAR)-NK cells that block TGFβ1 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGFβ1 and TGFβ receptor 1 and effectively disrupts TGFβ1's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGFβ1-mediated suppression of NK cell activity, thereby enhancing their metabolic function and cytotoxic response against pancreatic tumors. These CAR-NK cells exhibit potent antitumor capabilities, as evidenced in spheroid cultures with cancer-associated fibroblasts and in vivo mouse models. Our approach marks a substantial advancement in overcoming TGFβ1-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy.
Insights
This study developed novel chimeric antigen receptor (CAR)-NK cells that release a peptide to block transforming growth factor β1 (TGFβ1) signaling, enhancing antitumor immunity against pancreatic cancer.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Natural killer (NK) cell dysfunction, driven by tumor microenvironment's transforming growth factor β1 (TGFβ1), hinders cancer immunotherapy.
- TGFβ1 signaling suppresses NK cell activity, leading to immune evasion and poor patient outcomes in pancreatic cancer.
Purpose of the Study:
- To engineer chimeric antigen receptor (CAR)-NK cells capable of overcoming TGFβ1-mediated immune suppression.
- To develop a novel peptide-based strategy to disrupt TGFβ1 signaling within the tumor microenvironment.
Main Methods:
- Designed a peptide (P6) targeting mesothelin, derived from TGFβ1 receptor interaction sites.
- Engineered CAR-NK cells to release P6, thereby blocking TGFβ1 signaling.
- Assessed NK cell function, metabolic activity, and cytotoxicity in vitro and in vivo models.
Main Results:
- P6 peptide effectively interrupted the SMAD2/3 pathway in NK cells, reversing TGFβ1-induced suppression.
- Engineered CAR-NK cells demonstrated enhanced metabolic function and cytotoxic response against pancreatic tumor cells.
- CAR-NK cells showed potent antitumor activity in pancreatic cancer spheroid cultures and mouse models.
Conclusions:
- This novel CAR-NK cell therapy effectively overcomes TGFβ1-mediated immune evasion in pancreatic cancer.
- The P6 peptide-releasing CAR-NK cell strategy represents a promising advancement for cancer immunotherapy.
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