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

非小细胞肺癌（NSCLC），特别是具有激活KRAS突变的那些，通常是由肿瘤细胞增殖抑制剂（VEGF）抑制的。 对靶向药物无反应且预后不良。然而，免疫途径， 特别是PD-1/PD-L1通路阻断，最近改善了这些癌症的治疗，支持了 前提是逃避免疫破坏有助于非小细胞肺癌的发病机制。MUC 1-C是一种 一种致癌蛋白，在>80%的NSCLC中过表达，并与多种免疫信号传导相关 途径。 这项资助支持的工作表明，EGFR突变型NSCLC激活PD-1/PD-L1通路 并增加促炎细胞因子的产生。我们还表明MUC 1-C促进（i） 在NSCLC中通过EGFR活化的致癌信号传导，和（ii）在NSCLC中赋予EMT、自我更新和致瘤性。 KRAS突变型NSCLC。基于这些发现，我们已经产生了针对非脱落的新抗体。 MUC 1-C胞外结构域和胞质结构域抑制剂用于治疗性靶向MUC 1-C NSCLC细胞。 我们的初步观察结果表明，靶向MUC 1-C下调EGFR中PD-L1的表达， KRAS突变NSCLC细胞。我们还发现MUC 1-C缺陷与MUC 1-C的募集有关。 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 MUC 1-C在逃避免疫破坏中起重要作用，这将在以下研究中解决：（i） 人NSCLC细胞系，（ii）基因工程小鼠模型，和（iii）原发性NSCLC肿瘤。 具体目的：（1）探讨MUC 1-C在EGFR和KRAS中PD-L1通路活化中的作用 （2）确定MUC 1-C在巨噬细胞和T细胞的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）评估靶向 MUC 1-C以规避突变型EGFR和KRAS NSCL肿瘤中的免疫逃避，以及（4）评估新鲜的 切除/活组织检查的肺癌标本，并将MUC 1表达与T细胞和其他免疫细胞相关联 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.