Abstract 3650: STAT1 suppresses KRAS-driven lung adenocarcinoma depending on the tumor microenvironment

Lung cancer is responsible for the majority of cancer-related deaths worldwide. Within this severe disease lung adenocarcinoma (LUAD) belongs to the most common form of lung cancer. LUAD is highly correlated with KRAS mutations. Although, the first KRAS inhibitors entered into clinics recently, therapy resistance arises. Since KRAS-mutant LUAD is an inflammation driven disease, we focus on the JAK-STAT pathway as an alternative target. Preliminary data suggests that human KRAS-mutant LUAD is correlated to enriched JAK-STAT signaling, as well as STAT1 upregulation. Accordingly, we aimed to explore the tumorigenic functions of STAT1 in this form of lung cancer. Genetically engineered C57BL6/N mice which develop autochthonous KRAS-driven and P53-deficient LUAD proficient (KP) and deficient for STAT1 (KPS) were used. In a second mouse model expression of ovalbumin was induced in tumor cells, mimicking a neoantigen to increase immune infiltration in the presence (KPO) or absence of STAT1 (KPOS). Kaplan-Meyer analysis was performed to assess the overall survival. Tumor burden, as well as immune infiltration was analyzed in lungs 6 and 10 weeks after tumor induction via H&E, IHC and IF staining. Furthermore, the lung fluid was collected by bronchoalveolar lavage and used to profile inflammatory cytokines. Deletion of STAT1 reduced the survival in KRAS-driven LUAD mice only when ovalbumin was expressed. Tumor burden and tumor grades were increased in tumors lacking STAT1 at 6 and 10 weeks after tumor initiation. Surprisingly, although tumors of KPOS mice showed a decreased infiltration by T cells and CD4 T cells, CD8 T cell infiltration did not change, suggesting a tumor suppressive function of STAT1 via T cell exhaustion. Moreover, the macrophage attracting cytokine CCL9 secretion was upregulated and the number of tumor infiltrating, immunosuppressive macrophages was increased in KPOS mice. This data implicates a tumor suppressive function of STAT1 by secretion of cytokines that can recruit suppressive myeloid immune cells to the TME leading to CD4 T cell exclusion and CD8 T cell exhaustion. Further studies are needed on the changes in the immune infiltrating cells to explain the mechanism behind these intriguing findings. Citation Format: Christoph Trenk, Rebecca Sagmeister, Jaqueline Horvath, Monika Homolya, Andreea Corina Luca, Robert Eferl, Herwig Moll, Emilio Casanova. STAT1 suppresses KRAS-driven lung adenocarcinoma depending on the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3650.