WITHDRAWN: Oncogenic KRAS^G12Dextrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma

Abstract

Despite advancements in targeted and immunotherapies, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas, squamous cell carcinoma and large cell carcinoma. KRAS is commonly mutated in adenocarcinomas, with the most common point mutation being G12C (39%), followed by G12V (21%), G12D (17%), and G12A (10%). Notably, while KRASG12C is the most prevalent mutation in adenocarcinoma among former or current smokers (42%), KRASG12D is most common in patients who have never smoked (56%) [2]. Because nonsmokers have poorer prognosis, and mostly lack response to immunotherapy, we interrogated the immune changes in a previously described genetically engineered model of KrasG12D driven lung cancer. In this murine model, oncogenic Kras expression can be controlled genetically in the lung, allowing activation of oncogenic KrasG12D to initiate tumor growth, depletion of KrasG12D for tumor eradication, and re-activation of KrasG12D to model relapse. We demonstrate a KrasG12D dependent regulation of the tumor microenvironment depends on secreted factors derived from epithelial cells expressing oncogenic Kras, which regulates lung fibroblasts. Fibroblast derived secreted factors in turn drive an immune suppressive and tumor promoting phenotype in the lung, specifically through the polarization of macrophages. The identification of this oncogenic Kras-dependent secretome that supports lung tumor growth through crosstalk with the microenvironment provides new targets to develop alternative strategies for co-targeting KRAS mutant lung disease with Kras inhibitors or for treating recurring lung tumors.