Sunday, May 18, 2025
5/18/2025
Immune Checkpoint Regulation by the Integrated Stress Response Pathway in Lung Ca - PROJECT SUMMARY In recent years, there have been groundbreaking discoveries in the identification and therapeutic targeting of the PD-1/PD-L1 immune checkpoint axis. Lung cancer cells express high levels of Programmed Death Ligand 1 (PD-L1), a critical ligand for PD-1 on T cells. The PD-1/PD-L1 interaction allows tumor cells to directly suppress anti-tumor T cell activity, resulting in immune escape and tumor progression. Despite these advances, there remains a disconnect in patient expression of PD-L1 and treatment response. This underscores the critical need to understand mechanisms of PD-L1 upregulation, identify mechanisms of resistance to PD-1/PD-L1 therapy, and identify other immune checkpoints or pathways to pursue clinically in combination with this therapy. In response to tumor microenvironment stresses, such as hypoxia, heme deprivation, and amino acid starvation, cancer cells activate the integrated stress response (ISR). ISR activation allows cancer cells to escape these stresses through inhibition of global protein synthesis and increased translation of select mRNAs. The ISR has been shown to promote tumorigenesis, yet the role of the ISR in the translational control of immune checkpoint proteins has not been fully investigated. We recently demonstrated that ISR activation leads to potent induction of PD-L1 in non-small cell lung cancer (NSCLC) and suppression of anti-tumor immunity in vitro and in vivo, and we have new evidence that another immune checkpoint, CD155 (Cluster of differentiation 155), is induced upon ISR activation in NSCLC cells simultaneously with PD-L1. Our central hypothesis is that ISR activation causes tumor cell immune escape through translation of both PD-L1 and CD155. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: 1) Elucidate the mechanisms through which ISR activation promotes translation of CD155; 2) Determine the effect of ISR modulation on immune cell responses; 3) Examine the therapeutic efficacy of ISR inhibition in combination with PD-1 blockade and/or TIGIT (CD155’s immune cell receptor) blockade in mouse models. We will employ translational studies including luciferase reporter assays and ribosome profiling to dissect the mechanisms of ISR mediated PD-L1 and CD155 translational control in NSCLC cells. To determine the impact of ISR activation on immune cell responses, we will measure immune cell responses in co-culture studies and immunocompetent mouse models upon ISR activation. Finally, we will utilize mouse models and ISR inhibitors to determine whether ISR inhibition can suppress tumorigenesis by promoting an immune response and whether this can synergize with existing immune checkpoint therapies (Fig 1, model). Our proposed research is significant, because it will 1) uncover new regulatory circuits that govern immune checkpoint protein expression, 2) illuminate how insults experienced by cancer cells in the tumor microenvironment modulate the responses of immune cells, and 3) our studies will provide proof-of- concept for the development of new combination therapies for lung cancer.
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