TMC7抑制PKN2调控胰腺癌旁分泌促进肿瘤相关巨噬细胞极化：胰腺癌对PD-1单抗耐药的新机制

胰腺癌对PD-1单抗耐药是目前胰腺癌免疫治疗的关键瓶颈。M2型肿瘤相关巨噬细胞（TAM）促进胰腺癌对PD-1单抗耐药，而肿瘤微环境中调控TAM发生M2型极化的机制尚不明确。我们前期研究发现：1.跨膜通道蛋白7（TMC7）促进胰腺癌对PD-1单抗耐药；2.蛋白激酶N2（PKN2）通过抑制胰腺癌细胞旁分泌作用，抑制共培养的单核细胞向M2型巨噬细胞分化；3.TMC7抑制PKN2激酶活性。据此我们提出假设：TMC7通过抑制PKN2活性，激活胰腺癌细胞旁分泌作用，诱导TAM发生M2型极化，从而促进胰腺癌对PD-1单抗耐药。本研究拟从体内和体外水平，干预TMC7和PKN2表达，探究胰腺癌细胞旁分泌、M2型TAM极化及PD-1单抗疗效的改变，并进一步探究TMC7-PKN2-旁分泌轴的调控机制并在临床标本中验证。本研究有望阐明胰腺癌对PD-1单抗耐药的新机制，为胰腺癌免疫治疗提供新思路。

Pancreatic cancer resistance to PD-1 monoclonal antibody is the key bottleneck of immunotherapy forpancreatic cancer. M2-type tumor-associated macrophages (TAM) promote pancreatic cancer resistance to PD-1 monoclonal antibodies, and the mechanism of regulating M2-type polarization in TAM in the tumor microenvironment is not yet clear. Our previous research found that: 1. Transmembrane channel protein 7 (TMC7) promotes pancreatic cancer resistance to PD-1 monoclonal antibody; 2. Protein kinase N2 (PKN2) inhibits the differentiation of co-cultured monocytes into M2 macrophages by inhibiting the paracrine effect of pancreatic cancer cells; 3. TMC7 inhibits PKN2 kinase activity. Based on this, we hypothesize that TMC7 inhibits PKN2 activity, activates pancreatic cancer paracrine, and induces TAM to undergo M2-type polarization, resulting in PD-1 monoclonal antibody resistance. This study intends to intervene in the expression of TMC7 and PKN2 from in vivo and in vitro levels, to explore the changes of pancreatic cancer cell paracrine, M2 type TAM polarization, and PD-1 monoclonal antibody efficacy, and to further explore the role of TMC7-PKN2 axis in regulating pancreatic cancer paracrine function and involved mechanism. We will also verify the mechanism in clinical specimens. This study is expected to clarify the new mechanism of pancreatic cancer resistance to PD-1 monoclonal antibody, and provide new ideas for immunotherapy of pancreatic cancer.