MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer

非小细胞肺癌(NSCLC)，特别是那些具有激活的KRAS突变的癌症，通常是 对靶向药物无反应，预后较差。然而，免疫治疗方法， 尤其是PD-1/PD-L1通路的阻断，最近改善了这些癌症的治疗，支持 逃避免疫破坏是非小细胞肺癌发病机制的前提。MUC1-C是一种 在80%的非小细胞肺癌中高表达并与多种免疫信号有关的致癌蛋白 小路。 这项资助支持的工作表明，EGFR突变的NSCLC激活了PD-1/PD-L1途径 并增加促炎细胞因子的产生。我们还证明了MUC1-C促进(I) NSCLC中的致癌信号通过EGFR的激活，以及(Ii)赋予EMT，自我更新和致瘤性 KRAS突变体NSCLC。基于这些发现，我们产生了针对非脱发的新型抗体。 MUC1-C胞外结构域和胞浆结构域抑制剂对MUC1-C的靶向治疗作用 NSCLC细胞。 我们的初步观察表明，靶向MUC1-C下调了EGFR和 KRAS突变型NSCLC细胞。我们还发现，MUC1-C缺乏与招募 肿瘤相关巨噬细胞和浸润性T细胞表型的改变。我们的假设是 MUC1-C在逃避免疫破坏方面起着重要作用，这一点将在(I)的研究中得到解决。 人类非小细胞肺癌细胞系，(Ii)基因工程小鼠模型，以及(Iii)原发非小细胞肺癌肿瘤。 其具体目的是：(1)研究MUC1-C在EGFR和KRAS中PD-L1通路激活中的作用 突变的NSCLC细胞，(2)确定MUC1-C在巨噬细胞和T细胞募集和功能中的作用 在KRAS和EGFR突变型NSCLC的肿瘤微环境中，(3)评价靶向效应 MUC1-C用于规避突变的EGFR和KRAS NSCL肿瘤的免疫逃逸，以及(4)评估新鲜 肺癌切除/活检标本MUC1表达与T细胞和其他免疫细胞的相关性 肿瘤微环境中的浸润、免疫检查点基因表达和细胞因子分泌。

Non-small cell lung cancers (NSCLCs), particularly those with activating KRAS mutations, are often unresponsive to targeted agents and have a poor prognosis. However, immunotherapeutic approaches, particularly PD-1/PD-L1 pathway blockade, have recently improved the treatment of these cancers, supporting the premise that evasion of immune destruction contributes to NSCLC pathogenesis. MUC1-C is an oncogenic protein that is overexpressed in >80% of NSCLCs and is linked to multiple immune signaling pathways. Work supported by this grant has demonstrated that EGFR mutant NSCLCs activate the PD-1/PD-L1 pathway and increase production of proinflammatory cytokines. We have also shown that MUC1-C promotes (i) oncogenic signaling in NSCLCs via EGFR activation, and (ii) confers EMT, self-renewal and tumorigenicity in KRAS mutant NSCLCs. Based on these findings, we have generated novel antibodies against the non-shed MUC1-C extracellular domain and inhibitors of the cytoplasmic domain for therapeutic targeting of MUC1-C in NSCLC cells. Our preliminary observations indicate that targeting MUC1-C downregulates PD-L1 expression in EGFR and KRAS mutant NSCLC cells. We have also found that MUC1-C deficiency is associated with recruitment of tumor-associated macrophages and alterations in the infiltrating T-cell phenotype. Our hypothesis is that MUC1-C plays an important role in evading immune destruction, which will be addressed in studies of (i) human NSCLC cell lines, (ii) genetically engineered mouse models, and (iii) primary NSCLC tumors. The Specific Aims are: (1) To investigate the role of MUC1-C in PD-L1 pathway activation in EGFR and KRAS mutant NSCLC cells, (2) To define the role of MUC1-C in recruitment and function of macrophages and T-cells within the tumor microenvironment of KRAS and EGFR mutant NSCLC, (3) To evaluate the effects of targeting MUC1-C to circumvent immune evasion in mutant EGFR and KRAS NSCL tumors, and (4) To assess fresh resected/biopsied lung cancer specimens and correlate MUC1 expression with T-cell and other immune cell infiltration, immune checkpoint gene expression, and cytokine secretion in the tumor microenvironment.