Abstract 404P
Background
Lung cancer remains the leading cause of cancer-related deaths globally. Immunotherapies, particularly those targeting the PD-1/PD-L1 axis, have shown potential but often fail to produce significant responses due to the immunosuppressive tumor microenvironment (TME). This study investigates the synergistic potential of 41BB activation combined with irreversible electroporation (IRE) ablation to enhance anti-tumor immune responses in lung cancer.
Methods
We developed a protocol integrating IRE with PD-1 blockade, and 41BB agonists (IRE+Combo/41BB). IRE, a non-thermal ablation technique, induces widespread tumor cell death and releases tumor antigens, thereby triggering an immune response. The addition of PD-1 blockade reduces CD8+ T cell exhaustion. Crucially, 41BB agonists further boost CD8+ T cell function via the TRAF-ERK-PGC-1α pathway, which enhances mitochondrial biogenesis.
Results
IRE or Combo alone generated weak immune responses, but the combination of IRE with 41BB agonists markedly enhanced CTL responses, surpassing the effects of IRE combined with PD-1 inhibitors. The IRE+Combo+41BB regimen resulted in the most potent CTL responses, leading to significant primary tumor regression. Flow cytometry revealed an increased frequency of CD8+CD103+TCF1+ tissue-resident memory (TRM) cells in the TME and tumor-draining lymph nodes following IRE+Combo+41BB treatment. These TRM cells exhibited improved mitochondrial biogenesis and TNF1 nuclear localization, essential for sustained anti-tumor activity. Moreover, this combination therapy effectively reversed CD8+ T cell exhaustion, further amplifying the anti-tumor immune response.
Conclusions
Taken together, our data establish that the 41BB-agonist potentiates the efficacy of IRE+Combo-therapy for lung cancer by promoting not only TRM cell but also unexposed cDC1 responses, and emphasize the importance of targeting this promising molecular signal to improve current cancer IRE-ablation protocols.
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.