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41bb Significantly Enhances The Eradication Of Lung Cancer By Irreversible Electroporation Ablation
Yu Feng, Chen Fang, Haitao Ma.
the First Affiliated Hospital of Soochow University, Suzhou, China.
BACKGROUND: Lung cancer remains the leading cause of cancer-related deaths worldwide, despite advancements in therapeutic strategies. Immunotherapies, particularly those targeting the PD-1/PD-L1 pathway, have shown promise but often yield limited efficacy due to the immunosuppressive tumor microenvironment (TME). This study explores the synergistic potential of 41BB activation in conjunction with irreversible electroporation (IRE) ablation to enhance anti-tumor immune responses and eradicate lung cancer.
METHODS: We developed a novel protocol combining IRE with TLR3/9 agonists, PD-1 blockade, and 41BB agonists (IRE+Combo/41BB). IRE serves as a non-thermal ablation technique, inducing extensive tumor cell death and releasing tumor antigens, thereby initiating an immune response. The protocol's inclusion of TLR3/9 agonists promotes dendritic cell maturation and CD4 Th1 responses, while PD-1 blockade reduces CD8 T cell exhaustion. The pivotal addition of 41BB agonists enhances CD8 T cell function through the TRAF-ERK-PGC-1α pathway, boosting mitochondrial biogenesis .Flow cytometry staining was used to detect changes in the immune cell populations in the tumor microenvironment and tumor-draining lymph nodes of mice treated with the novel regimen and untreated mice. In this study, we utilized a custom-made IRE device tailored for small animal models, delivering pulses at 1200 V/cm with a 90 μs duration and 1 Hz repetition frequency. The protocol was evaluated in lung cancer models, focusing on its capacity to induce cytotoxic T lymphocyte (CTL) responses and tumor regression.
RESULTS: IRE or Combo alone elicited weak immune responses. However, the combination of IRE with 41BB agonists significantly improved CTL responses, surpassing the effects of IRE combined with CpG/pIC or PD-1 blockade. The IRE+Combo+41BB protocol yielded the most potent CTL responses, leading to effective primary tumor eradication. Flow cytometry analysis revealed that the IRE+Combo+41BB treatment increased the frequency of CD8+CD103+TCF1+ tissue-resident memory (TRM) cells in the TME and tumor-draining lymph nodes. These TRM cells exhibited enhanced mitochondrial biogenesis and TNF1 nuclear localization, critical for sustained anti-tumor activity. Additionally, this combination therapy effectively rescued CD8 T cell exhaustion, further amplifying the anti-tumor immune response.
CONCLUSIONS: IRE+Combo/41BB protocol represents a promising therapeutic approach for lung cancer, leveraging the synergistic effects of IRE-induced tumor antigen release and 41BB-mediated T cell activation. This strategy not only enhances CTL responses but also promotes the formation of TRM cells, providing a robust and durable anti-tumor immune response. Further clinical evaluation is warranted to translate these findings into effective treatments for lung cancer patients.
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