Resumen de Evaluation of type I interferon pathway in KRAS-driven lung adenocarcinoma and its potential synergy with immunotherapy
Lung cancer is the leading cause of cancer-related death worldwide, with lung adenocarcinoma (LUAD) being the main subtype. Importantly, alveolar type II cells (AT2) are considered the cells of origin of LUAD. KRAS appears mutated in up to 30% of the cases of LUAD and serves as an oncogenic driver promoting tumor progression. In addition to the mutations in KRAS, cooccurring mutations in the TRP53 or STK11 genes lead to more aggressive tumors due to the lossof-function of the p53 and LKB1 tumor suppressors, respectively. Furthermore, it is common the coexistence of different subpopulations of tumor cells within the tumor mass, referred to as intratumor heterogeneity. This adds a layer of complexity for LUAD treatment and is responsible of poorer overall survival and therapeutic failure. Importantly, driver alterations that occur during early stages of LUAD development are likely to persist in tumor cells over time. Thus, researchers have developed genetically engineered mouse models that faithfully recapitulate the disease. In order to identify early alterations that could be therapeutically utilized, we performed singlecell RNAseq of AT2 cells only 4 weeks post-induction of KRASG12V oncogenic expression, and wild type AT2 control cells. Bioinformatic analyses showed that the type I interferon (IFN) pathway is impaired in KRAS mutant AT2 cells compared to wild type cells. Moreover, these findings can be extrapolated to more advanced tumors lacking the p53 or LKB1 tumor suppressors, as well as KRAS-driven human LUAD. Next, we investigated whether stimulation of the type I INF pathway could result in a therapeutic benefit. We found that expression of IFN-β and a constitutively active mutant version of STING, reduced the ability of KRAS mutant lung tumor cell lines to form colonies in vitro. Additionally, in vivo studies inducing the expression of both proteins in subcutaneous tumors raised in immunocompetent mice resulted in significant intratumor immune cell population changes, especially in CD8 pos T cells. Since PD-L1 expression is induced upon type I IFN pathway stimulation, we combined expression of IFN-β or mutant STING with an anti-PD-1 treatment. Stimulation of type I IFN pathway reduced tumor growth and this effect was enhanced in the combined treatment. Finally, we treated mice bearing endogenous KRAS driven lung tumors with poly(I:C) to stimulate the type I IFN pathway, observing a delay in tumor growth when combining with anti-PD-1 treatment. In conclusion, we demonstrated that impairment of the type I IFN pathway is a general feature of KRAS-driven LUAD that constitutes a therapeutically exploitable vulnerability. Indeed, several clinical trials in non-small cell lung cancer patients are currently being conducted to study the benefit of using IFN-based therapies in combination with immune checkpoint inhibitors
