Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, United States.
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States.
Cancer Res Commun. 2022 Jul;2(7):725-738. doi: 10.1158/2767-9764.crc-22-0069. Epub 2022 Jul 27.
Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiation therapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell-based immunotherapy against pancreatic cancer, its combination with radiation therapy hold greater therapeutic benefit.
胰腺癌是致命率最高的癌症之一，目前的免疫疗法策略对此并不有效。在此，我们分析了癌症基因组图谱中胰腺癌样本肿瘤微环境中的免疫细胞组成，发现肿瘤内 NK 细胞的存在与存活率相关。随后的分析还表明，在临床上高比例的胰腺癌和胰腺癌的临床前模型中，NK 细胞被排除在微环境之外。从机制上讲，NK 细胞的排除部分受到补体 C3a 和其受体信号的调节。抑制 C3a 受体可增强 NK 细胞在同种小鼠胰腺癌模型中的浸润，从而导致肿瘤生长延迟。然而，NK 细胞介导的肿瘤生长抑制本身不足以完全消退肿瘤，但与放射治疗联合使用时则具有更大的治疗益处。我们的研究结果表明，尽管抑制 C3a 是增强针对胰腺癌的基于 NK 细胞的免疫治疗的一种很有前途的方法，但与放射治疗联合使用则具有更大的治疗益处。
