Patched 1-interacting Peptide Represses Fibrosis in Pancreatic Cancer to Augment the Effectiveness of Immunotherapy
Patched 1-interacting Peptide Represses Fibrosis in Pancreatic Cancer to Augment the Effectiveness of Immunotherapy
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DOI：
10.1097/cji.0000000000000305
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发表时间：
2020-05-01
影响因子：
3.9
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
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作者：
Oyama, Yasuhiro;Onishi, Hideya;Nakamura, Masafumi
胰腺导管腺癌（PDAC）对免疫治疗具有耐药性。作为抵抗的一个因素，这种癌症的致密纤维化作为一个屏障来抑制免疫细胞浸润到肿瘤中。我们研究了一种刺猬信号抑制剂，补丁1相互作用肽对纤维化、免疫细胞浸润和PDAC免疫治疗作用的影响。我们发现这种肽抑制癌症相关成纤维细胞和癌细胞的增殖和迁移。此外，这种肽减少了癌症相关成纤维细胞中细胞外基质和转化生长因子β 1的产生，并诱导PDAC细胞中HLA-ABC和淋巴细胞中干扰素- γ的表达。在体内，肽抑制PDAC的纤维化，增加免疫细胞向肿瘤的浸润。这种肽和抗程序性死亡-1抗体的结合增强了抗肿瘤效果，并且这种结合在使用癌细胞和自体淋巴细胞的实验中显示出相同的效果。这些结果表明，除了具有直接的抑瘤作用外，Patched 1相互作用肽还可以通过减少PDAC的纤维化来增加免疫细胞的浸润，从而增强免疫治疗的效果。因此，用这种肽治疗可能是一种具有两种不同机制的新疗法：直接抑制肿瘤和增强对PDAC的免疫反应。
Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor beta 1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-gamma in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.