Department of Surgery B, Weizman 6, Tel-Aviv 6423906, Israel; Laboratory of Surgical Oncology, Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Trauma Unit, Wolfson Medical Center, Holon, Israel.
Int Immunopharmacol. 2023 Mar;116:109829. doi: 10.1016/j.intimp.2023.109829. Epub 2023 Feb 7.
Peritoneal metastases of colorectal carcinoma origin (PM-CRC) are treated by cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC). However, the majority of patients recur, calling for novel treatments. We explored the immunogenic changes induced by HIPEC and the possibility to use thymosin α1 (Tα1) as an immune-stimulatory agent.
We used an experimental murine model of PM-CRC combined with mitomycin (MMC)-based HIPEC. We determined immune cell infiltration into tumor metastases after HIPEC administration by means of immunohistochemistry, and determined immunogenic cell death signals in tumor cells by real-time polymerase chain reaction.
Mice with PM-CRC treated by HIPEC had increased overall survival (OS) compared to sham-treated mice (median OS 22.8 vs 18.9 days, respectively; P < 0.001). HIPEC induced increased infiltration of CD4+, CD8+, CD68 + and CD20 + cells into omental and visceral metastases at a magnitude of 40-100 %. We searched for potential immune signals induced by HIPEC by determining its effects on known immunogenic cell death proteins (heat-shock protein [HSP]-70, HSP-90 and calreticulin). HIPEC significantly increased HSP-90 mRNA expression (2.37 ± 1.5 vs 1-fold change, P < 0.05). The OS of Tα1 treated mice significantly improved compared to HIPEC-treated mice (16.3 ± 0.8 vs 14.1 ± 0.6 days, respectively, P = 0.02) and vs sham (11.8 ± 0.8 days, P = 0.007).
HIPEC induced immunogenic changes that led to increased immune cell infiltration. These changes were further augmented by Tα1 treatment. Future studies aimed at optimizing Tα1 treatment should focus upon the immune response it evokes.
结直肠癌腹膜转移（PM-CRC）通过细胞减灭术和腹腔热灌注化疗（HIPEC）治疗。然而，大多数患者会复发，需要新的治疗方法。我们探讨了 HIPEC 诱导的免疫原性变化以及使用胸腺肽 α1（Tα1）作为免疫刺激剂的可能性。
我们使用了一种结直肠癌腹膜转移的实验性小鼠模型，结合了丝裂霉素（MMC）基础的 HIPEC。我们通过免疫组织化学检测 HIPEC 给药后肿瘤转移灶中的免疫细胞浸润情况，并通过实时聚合酶链反应检测肿瘤细胞中的免疫原性细胞死亡信号。
与假手术治疗的小鼠相比，接受 HIPEC 治疗的 PM-CRC 小鼠的总生存期（OS）显著延长（中位 OS 分别为 22.8 和 18.9 天，P<0.001）。HIPEC 诱导的 CD4+、CD8+、CD68+和 CD20+细胞浸润腹膜和内脏转移灶的程度为 40-100%。我们通过确定其对已知免疫原性细胞死亡蛋白（热休克蛋白 [HSP]-70、HSP-90 和钙网蛋白）的影响来寻找 HIPEC 诱导的潜在免疫信号。HIPEC 显著增加了 HSP-90 mRNA 的表达（2.37±1.5 倍变化，P<0.05）。与 HIPEC 治疗的小鼠相比，Tα1 治疗的小鼠的 OS 显著改善（16.3±0.8 天 vs 14.1±0.6 天，分别，P=0.02），与假手术相比（11.8±0.8 天，P=0.007）。
HIPEC 诱导了免疫原性变化，导致免疫细胞浸润增加。Tα1 治疗进一步增强了这些变化。未来旨在优化 Tα1 治疗的研究应侧重于它引发的免疫反应。
