Vigneron Clara, Mirouse Adrien, Merdji Hamid, Rousseau Christophe, Cousin Clément, Alby-Laurent Fanny, Mira Jean-Paul, Chiche Jean-Daniel, Llitjos Jean-François, Pène Frédéric
Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.
Université Paris Descartes, Paris, France.
Oncoimmunology. 2019 Jul 19;8(11):e1641391. doi: 10.1080/2162402X.2019.1641391. eCollection 2019.
Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in ( nor in mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1 MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.
脓毒症诱导的免疫功能障碍可能会影响恶性肿瘤的生长。在从脓毒症中恢复的小鼠中进行的脓毒症继发癌症的肿瘤移植序贯模型表明，脓毒症后的免疫抑制环境能够促进肿瘤生长。我们在此通过反向的癌症继发脓毒症实验模型，探讨了脓毒症对已建立的恶性肿瘤的影响。先前接种了MCA205纤维肉瘤细胞的小鼠，通过盲肠结扎和穿刺诱导的多微生物腹膜炎或内毒素休克接受脓毒症挑战。通过肿瘤浸润免疫细胞的分布以及细胞毒性细胞的功能来评估抗肿瘤免疫反应。与假手术相比，多微生物脓毒症抑制了野生型（WT）小鼠的恶性肿瘤生长，但在（此处原文缺失相关基因信息）小鼠和（此处原文缺失相关基因信息）小鼠中均未观察到这种抑制作用。在WT小鼠中，脂多糖（LPS）刺激后也观察到了类似的肿瘤生长抑制，这表明Tlr4在这种情况下具有调节作用。MCA205细胞上主要组织相容性复合体（MHC）I类分子的低表达表明自然杀伤（NK）细胞参与了脓毒症诱导的肿瘤抑制。对患有癌症的小鼠施加脓毒症刺激促进了NK细胞产生干扰素γ和脱颗粒的主要抗肿瘤功能。当与MHC1 MCA205或YAC - 1细胞一起培养时，从脓毒症小鼠获得的NK细胞的抗肿瘤特性会增强。这些结果表明，根据序贯实验模型，脓毒症可能对肿瘤生长具有双重影响。当应用于患有癌症的小鼠时，脓毒症通过增强NK细胞的抗肿瘤功能以Tlr4依赖的方式阻止肿瘤生长。
