School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Front Immunol. 2024 Nov 1;15:1445513. doi: 10.3389/fimmu.2024.1445513. eCollection 2024.
The characteristics of the tumor immunosuppressive microenvironment represent a major challenge that limits the efficacy of immunotherapy. Our previous results suggested that cryo-thermal therapy, a tumor ablation system developed in our laboratory, promotes macrophage M1-type polarization and the complete maturation of DCs to remodel the immunosuppressive environment. However, the cells that respond promptly to CTT have not yet been identified. CTT can cause extensive cell death and the release of danger-associated molecular patterns and antigens. Neutrophils are the first white blood cells recruited to sites of damage and acute inflammation. Therefore, we hypothesized that neutrophils are the initial cells that respond to CTT and are involved in the subsequent establishment of antitumor immunity.
In this study, we examined the kinetics of neutrophil recruitment after CTT via flow cytometry and immunofluorescence staining and explored the effect of neutrophils on the establishment of systemic antitumor immunity by neutrophil depletion and co-culture assays.
We found that CTT led to a rapid and strong proinflammatory neutrophil response, which was essential for the long-term survival of mice. CTT-induced neutrophils promoted the activation of monocytes via reactive oxygen species and further upregulated the expression of IFN-γ and cytotoxic molecules in T and NK cells. Adoptive neutrophil transfer further enhanced the antitumor efficacy of CTT in tumor models of spontaneous and experimental metastasis.
These results reveal the important role of neutrophil‒monocyte interactions in the development of anti-tumor immunity and highlight that CTT could be used as an immunotherapy for targeting neutrophils and monocytes to enhance antitumor immunity.
肿瘤免疫抑制微环境的特征是限制免疫疗法疗效的主要挑战。我们之前的结果表明，我们实验室开发的冷冻-热疗肿瘤消融系统促进巨噬细胞 M1 型极化和 DC 的完全成熟，从而重塑免疫抑制环境。然而，对 CTT 迅速作出反应的细胞尚未确定。CTT 可引起广泛的细胞死亡以及危险相关分子模式和抗原的释放。中性粒细胞是第一批被募集到损伤和急性炎症部位的白细胞。因此，我们假设中性粒细胞是对 CTT 作出反应的初始细胞，并参与随后建立抗肿瘤免疫。
在这项研究中，我们通过流式细胞术和免疫荧光染色检查了 CTT 后中性粒细胞募集的动力学，并通过中性粒细胞耗竭和共培养实验探讨了中性粒细胞对建立全身抗肿瘤免疫的影响。
我们发现 CTT 导致迅速而强烈的促炎中性粒细胞反应，这对于小鼠的长期存活至关重要。CTT 诱导的中性粒细胞通过活性氧促进单核细胞的激活，并进一步上调 T 和 NK 细胞中 IFN-γ 和细胞毒性分子的表达。过继性中性粒细胞转移进一步增强了 CTT 在自发性和实验性转移肿瘤模型中的抗肿瘤疗效。
这些结果揭示了中性粒细胞-单核细胞相互作用在抗肿瘤免疫发展中的重要作用，并强调 CTT 可作为一种免疫疗法，靶向中性粒细胞和单核细胞以增强抗肿瘤免疫。
