Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Lung cancer remains both prevalent and deadly, emphasizing the need for continued research and therapy development. Advances in immunotherapeutic technologies, including check-point inhibitors such as anti-PD-1 monoclonal antibody therapy, have shown great promise in treating lung cancer patients. Unfortunately, not all patients respond. Recent clinical studies have linked anti-PD-1 therapy resistance with specific combinations of somatic tumor mutations. Notably, patients with KRAS-driven lung adenocarcinomas lacking functional STK11 suffer a worse prognosis, increased rates of metastasis, and marked resistance to anti-PD-1 therapy. Why STK11 loss of function (LoF) correlates with resistance to anti-PD-1 therapy remains unclear. Serine Threonine Kinase 11 (STK11) encodes an important tumor suppressor gene frequently mutated in KRAS-driven lung adenocarcinomas. Our work in human lung cancer cell lines supports STK11-loss-dependent transcriptional induction of tumor cytokines as one mechanism that might impact anti-PD-1 therapy resistance. Specifically, RNAseq analysis indicates activation of Yes-associated protein 1 (YAP1) and Nuclear Factor Kappa B (NFkB) transcription networks occur upon STK11 loss. YAP1 is the ultimate effector in the HIPPO signaling axis, a pathway critical for regulating organ size during development. While YAP1 has previously been linked with regulating tumor cytokine expression, whether its activity is directly regulated by STK11 has yet to be established. NFkB is a master transcription factor essential for regulating numerous cytokines, but as with YAP1, how STK11 might regulate NFkB activity remains unaddressed. We hypothesize that STK11 loss leads to anti-PD-1 therapy resistance by altering immune cell recruitment to the tumor microenvironment via altered tumor cytokine signaling. The workplan we present aims to characterize differential immune cell recruitment in an inducible mouse model of lung cancer as a function of STK11 status and tumor transcriptome. We will leverage immune competent, genetically engineered mice that develop inducible KRAS-driven or KRAS/STK11 LoF lung adenocarcinomas to directly characterize the correlation between tumor genotype, tumor transcriptome, and differential immune cell recruitment. We will then utilize this model to assess strategies for reversing anti-PD-1 therapy resistance. Specifically, we will evaluate antagonizing candidate transcriptional networks downstream of STK11 loss, including YAP1 and NFkB, as strategies to restore an anti-tumor immune microenvironment, potentially rescuing anti-PD1 efficacy in STK11 null tumors. To accomplish this, we will define the extent of STK11-dependent anti-PD-1 resistance displayed by our mice compared with tumors driven by KRAS alone. We will then evaluate whether antagonizing candidate networks reverses the STK11-LoF transcriptional phenotype, and in turn restores the immune cell compliment observed in STK11 WT tumors.
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