Department of Gastroenterological Surgery, Oslo University Hospital The Radium Hospital, Oslo, Norway.
Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Ann Surg Oncol. 2021 Sep;28(9):5252-5262. doi: 10.1245/s10434-021-10022-0. Epub 2021 May 21.
Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial cell adhesion molecule, and kills cancer cells by distinct mechanisms, simultaneously causing immune activation by induction of immunogenic cell death (ICD).
Systemic and local cytokine responses were analyzed in serum and intraperitoneal fluid samples collected the first three postoperative days from clinically comparable patients undergoing CRS-HIPEC with (n = 12) or without (n = 26) intraperitoneal instillation of MOC31PE. A broad panel of 27 pro- and antiinflammatory interleukins, chemokines, interferons, and growth factors was analyzed using multiplex technology.
The time course and magnitude of the systemic and local postoperative cytokine response after CRS-HIPEC were highly compartmentalized, with modest systemic responses contrasting substantial intraperitoneal responses. Administration of MOC31PE resulted in changes that were broader and of higher magnitude compared with CRS-HIPEC alone. Significantly increased levels of innate proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF) as well as an interesting time response curve for the strong T-cell stimulator interferon (IFN)-γ and its associated chemokine interferon gamma-induced protein/chemokine (C-X-C motif) ligand 10 (IP-10) were detected, all associated with ICD.
Our study revealed a predominately local rather than systemic inflammatory response to CRS-HIPEC, which was strongly enhanced by MOC31PE treatment. The MOC31PE-induced intraperitoneal inflammatory reaction could contribute to improve remnant cancer cell killing, but the mechanisms remain to be elucidated in future studies.
尽管进行了广泛的细胞减灭术和腹腔热灌注化疗（CRS-HIPEC），但大多数可切除的结直肠癌腹膜转移患者仍会出现疾病复发。MOC31PE 免疫毒素正在被探索作为这些患者的一种新的治疗选择。MOC31PE 靶向癌相关上皮细胞黏附分子，通过不同的机制杀死癌细胞，同时通过诱导免疫原性细胞死亡（ICD）引起免疫激活。
分析了接受 CRS-HIPEC 治疗的临床可比性患者术后第 1-3 天收集的血清和腹腔液样本中的系统和局部细胞因子反应。使用多重技术分析了广泛的 27 种促炎和抗炎白细胞介素、趋化因子、干扰素和生长因子。
CRS-HIPEC 后全身和局部细胞因子反应的时间过程和幅度高度分隔，全身反应适度，与腹腔内反应显著不同。与单独 CRS-HIPEC 相比，MOC31PE 的给药导致的变化更广泛，幅度更大。检测到先天促炎细胞因子（如白细胞介素（IL）-6、IL-1β 和肿瘤坏死因子（TNF））的水平显著增加，以及干扰素（IFN）-γ及其相关趋化因子干扰素γ诱导蛋白/趋化因子（C-X-C 基序）配体 10（IP-10）的有趣时间反应曲线，所有这些都与 ICD 相关。
我们的研究揭示了 CRS-HIPEC 主要是局部而非全身炎症反应，MOC31PE 治疗强烈增强了这种反应。MOC31PE 诱导的腹腔内炎症反应可能有助于提高残留癌细胞的杀伤作用，但在未来的研究中仍需要阐明其机制。
