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。

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.