肿瘤微环境介导单抗靶向药物抵抗的机制及其对策

Trastuzumab and Cetuximab which recognize the human epidermal growth factor receptors (HER) represent a class of monoclonal antibody drugs successfully used for clinical cancer treatment. Nevertheless, the frequent unresponsiveness of patients has led to limited therapeutic efficacy of these antibodies. Despite the established key role of tumor microenvironment in regulating antibody-elicited antitumor immunity, the underlying mechanisms remain largely unknown. We found in pilot experiments that TGF-β signaling is critically involved in Trastuzumab resistance, and that drug-refractory tumor cells express inhibitory ligands for tumoricidal immunity and recruit regulatory T cells. Based on these findings, the present study is designed to screen the differentially expressed cytokines in the microenvironment of antibody-resistant tumors, which is followed by the analysis of the expression profiles of immune inhibitory molecules (IIM) regulated by these cytokines. The effect of IIM-mediated tumor cell―NK cell interaction on antibody-induced ADCC, and the suppression of antitumor adaptive immunity by IIM-recruited regulatory immune cells will be addressed. Subsequently. the refractory tumors will be targeted by approaches involving the blockade of the key mediators of drug resistance and the generation of chimeric antigen receptor-expressing lymphocytes. This study will beneficial to understanding the molecular basis of crosstalk among tumor, stromal and immune cells underlying drug resistance, thus providing rationale for the development of novel strategies to overcome tumor resistance to monoclonal antibody pharmaceuticals.

以靶向人表皮生长因子受体（HER）的Trastuzumab和Cetuximab为代表的单抗类药物已成功应用于肿瘤治疗，但临床上广泛存在的耐药极大降低了其疗效；肿瘤微环境对单抗诱导的抗肿瘤免疫反应发挥关键调控作用，但具体机制并不清楚。在前期发现TGF-β信号调控Trastuzumab耐药，以及耐药肿瘤细胞表达免疫抑制性配体和募集调节性T细胞的基础上，我们拟从肿瘤微环境中细胞因子的改变入手，分析其对耐药肿瘤中免疫抑制分子表达的调控作用，探讨这些免疫抑制分子介导的肿瘤和NK细胞相互作用对抗体引发的ADCC的影响，以及通过募集免疫调节细胞对抗肿瘤特异性免疫的抑制作用；在此基础上，通过靶向沉默介导耐药的关键节点分子、嵌合抗原受体基因修饰淋巴细胞等策略对耐药肿瘤进行干预。本研究将为系统阐明调控单抗类抗肿瘤药物耐药的肿瘤、基质和免疫细胞相互作用规律提供理论依据，并为逆转耐药提供新的思路。

以靶向人表皮生长因子受体2（HER2）的Trastuzumab为代表的单抗类药物已成功应用于肿瘤治疗，但临床上广泛存在的耐药极大降低了其疗效；肿瘤微环境对单抗诱导的抗肿瘤免疫反应发挥关键调控作用，但具体机制并不清楚。在前期发现TGF-β信号调控Trastuzumab耐药，以及耐药肿瘤细胞表达免疫抑制性配体和募集调节性T细胞的基础上，本项目从肿瘤微环境中细胞因子的改变入手，分析了耐药肿瘤中免疫抑制分子表达的调控作用，探讨这些免疫抑制分子介导的肿瘤和NK细胞相互作用对抗体引发的ADCC的影响，以及通过募集免疫调节细胞对抗肿瘤特异性免疫的抑制作用；在此基础上，通过靶向沉默介导耐药的关键节点分子、嵌合抗原受体基因修饰淋巴细胞等策略对耐药肿瘤进行干预。我们的研究首次发现非经典MHC I类分子HLA-G通过与NK细胞受体KIR2DL4结合促进HER2阳性乳腺癌细胞对Trastuzumab产生耐药的新机制；首次发现m6A修饰在巨噬细胞调控肿瘤发生和转移中的作用，并证明巨噬细胞中m6A修饰可以作为一个潜在的免疫治疗靶点；发现FoxM1/STMN1转录信号的异常活化是导致肿瘤基因组不稳定和癌细胞异常增殖的关键分子事件；发现EZH2-miR-29/30-LOXL4信号轴可以通过调控免疫微环境参与肿瘤的发生转移，为EZH2表观遗传修饰机制与细胞外基质改变以及免疫微环境之间的联系提供了明确证据；建立了靶向HER2的人源化单链抗体，并成功应用于Trastuzumab耐药的HER2阳性肿瘤，以上研究成果发表于Nat Commun；Signal Transduct Target Ther；Theranostics；Biomaterials等杂志，并获批授权3项国家发明专利。本研究为系统阐明单抗类抗肿瘤药物耐药的肿瘤、基质和免疫细胞相互作用规律提供了理论依据，并为逆转耐药提供了新的思路。