Lung cancer is the leading cause of cancer-related deaths worldwide due to its aggressive nature, with oncogenic mutations in EGFR being one of the most common genetic drivers of this disease. In particular, lung adenocarcinoma (LUAD), the most common subtype of lung cancer, often forces patients to endure significant physiological stress, leading to the production of cortisol. However, the consequences of physiological glucocorticoid receptor (GR) mediated signaling in LUAD is not well described. Interestingly, GR expression is downregulated in tumors in comparison to heathy parenchyma with lower GR expression correlating with poorer patient survival outcome.

We use autochthonous mouse models of lung tumorigenesis to study the impact of tumor cell intrinsic GR signaling in EGFR driven lung tumors, supplemented by in vitro experiments.

GR deletion in EGFR driven lung tumor cells promotes tumor initiation and progression, resulting in drastically reduced survival, in immunocompetent mice. In vitro, however, GR deficient tumor cells proliferate slower, and also following transplantation into immunodeficient mice. This discrepancy suggests a pivotal role of the tumor microenvironment in GR’s tumor-suppressive effects. Indeed, loss of GR results in an immunosuppressive microenvironment characterized by lower cytotoxic and helper T cells and increased myeloid derived cells and tumor associated macrophages. To stronger emphasize the impact of the immune micronenvironnment, we then implemented more immunogenenic mouse models where cancer cells express the neoantigen ovalbumin. Intriguingly, mice harboring GR deficient, OVA expressing tumors exhibited increased tumor burden not only compared to GR and OVA expressing controls, but also compared to the non-OVA, GR deficient group. This suggests that GR deficient tumor cells hijack infiltrating T cells to boost tumorigenesis. In addition, by multiplex cytokine assay, we discovered that bronchoalveolar lavage derived from tumor intrinsic deficient GR mice present an higher level in TGFB and CXCL12 which might promote the tumor immunosuppressive microenvironnement and the tumor growth.

We identified tumor intrinsic GR signaling as an powerful tumor suppressor in EGFR driven LUAD, with its loss resulting in a tumor promoting tumor microenvironment. These findings may have major impact on current treatment strategies, including the outcome of osimertinib therapy.