Lung cancer is the leading cause of mortality by cancer worldwide. Non-small cell lung cancer is the most common type of lung cancer and mutations in the KRAS gene are frequently found in this pathology. While immune checkpoint inhibitors are providing new hope for lung cancer care, only a subset of patients show durable benefit from these new therapies designed to drive an efficient anti-tumor immune response. Hence, it is crucial to better understand the mechanisms through which the tumor immune microenvironment is established in lung tumors. Using bioinformatics, we observed that high expression of the STimulator of INterferon Gene (STING) associates with a longer overall survival specifically in KRAS mutant cancer patients. In lung cancer cell lines, STING expression is linked to interferon response and epithelial-to-mesenchymal transition. Because STING activation in immune cells of the tumor microenvironment using specific agonists is an emerging strategy to trigger an anti-tumor immune response, we took advantage of two transplantable models of Kras driven lung cancer, expressing high or low levels of STING, to investigate the function of STING directly in cancer cells in vivo. We observed that high-STING expression and constitutive STING signaling were critical for transplanted tumor formation rather than playing a major role in tumor immunogenicity. Besides, low-STING expression in cancer cells is associated with an immunosuppressive tumor microenvironment characterized by the accumulation of tumor promoting SiglecF+ neutrophils and CD103+ regulatory T cells. In that model, knocking out STING increased the early response to anti-PD1 treatment. We conclude that low-STING expression in cancer cells might confer them an independence from pro-inflammatory signals and a greater immunosuppressive capability and aggressiveness.

中文翻译：

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在可移植的KrasG12D / P53ko肺癌模型中STING的低表达有助于SiglecF +中性粒细胞和CD103 + Treg在肿瘤中的蓄积

肺癌是全世界癌症致死的主要原因。非小细胞肺癌是最常见的肺癌类型，在这种病理中经常发现KRAS基因突变。尽管免疫检查点抑制剂为肺癌的治疗提供了新希望，但只有一小部分患者从这些旨在驱动有效抗肿瘤免疫反应的新疗法中获得持久的收益。因此，至关重要的是更好地了解在肺肿瘤中建立肿瘤免疫微环境的机制。使用生物信息学，我们观察到干扰素基因STimulator（STING）的高表达与更长的总生存期有关，特别是在KRAS突变癌症患者中。在肺癌细胞系中，STING表达与干扰素反应和上皮-间质转化有关。由于使用特定的激动剂在肿瘤微环境的免疫细胞中激活STING是触发抗肿瘤免疫反应的新兴策略，因此我们利用两种可移植的Kras驱动的肺癌模型（表达高或低水平的STING）进行研究，直接在体内癌细胞中发挥作用 我们观察到高STING表达和组成性STING信号对于移植的肿瘤形成至关重要，而不是在肿瘤免疫原性中起主要作用。此外，癌细胞中STING的低表达与免疫抑制性肿瘤微环境有关，其特征在于促进肿瘤的SiglecF +中性粒细胞和CD103 +调节性T细胞的积累。在该模型中，敲除STING可提高对抗PD1治疗的早期反应。