宿主遗传学和肿瘤微环境决定了中性粒细胞在小鼠肿瘤模型中的功能影响。
Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models.
机构信息
Medical Oncology, Oncode institute, Leiden University Medical Center, Leiden, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
出版信息
J Immunother Cancer. 2020 Sep;8(2). doi: 10.1136/jitc-2020-000877.
BACKGROUND
Neutrophils have been reported to have protumor, antitumor or neutral effects in cancer progression. The underlying causes for this functional variability are not clear.
METHODS
We studied the role of neutrophils in six different mouse tumor models by intratumoral injection of antimicrobial peptides or vaccination. Changes in systemic and intratumoral immune cells were analyzed by flow-cytometry and mass-cytometry. The role of neutrophils was studied by antibody-mediated neutrophil depletion. Neutrophils from different mouse strains were compared by RNA sequencing.
RESULTS
The antimicrobial peptide Omiganan reduced the growth of TC-1 tumors in BL/6 mice and CT26 tumors in BALB/c mice. No significant effects were observed in B16F10, MC38 and 4T1 tumors. Growth delay was associated with increased abundance of neutrophils in TC-1 but not CT26 tumors. Systemic neutrophil depletion abrogated Omiganan efficacy in TC-1 but further reduced growth of CT26, indicating that neutrophils were required for the antitumor effect in TC-1 but suppressed tumor control in CT26. Neutrophils were also required for a therapeutic vaccine-induced T-cell mediated control of RMA tumors in BL/6 mice. Clearly, the circulating and intratumoral neutrophils differed in the expression of Ly6G and CD62L, between TC-1 and CT26 and between blood neutrophils of tumor-naïve BL/6 and BALB/c mice. RNA-sequencing revealed that neutrophils from BL/6 mice but not BALB/c mice displayed a robust profile of immune activation, matching their opposing roles in TC-1 and RMA versus CT26.
CONCLUSIONS
Neutrophil functionality differs strongly between mouse strains and tumor types, with consequences for tumor progression and therapy.
背景
中性粒细胞在癌症进展中具有促进肿瘤、抗肿瘤或中性作用。其功能变异性的根本原因尚不清楚。
方法
我们通过肿瘤内注射抗菌肽或疫苗研究了中性粒细胞在六种不同小鼠肿瘤模型中的作用。通过流式细胞术和质谱细胞术分析系统和肿瘤内免疫细胞的变化。通过抗体介导的中性粒细胞耗竭研究中性粒细胞的作用。通过 RNA 测序比较不同小鼠品系的中性粒细胞。
结果
抗菌肽 Omiganan 减少了 BL/6 小鼠 TC-1 肿瘤和 BALB/c 小鼠 CT26 肿瘤的生长。在 B16F10、MC38 和 4T1 肿瘤中未观察到明显作用。生长延迟与 TC-1 肿瘤中中性粒细胞丰度的增加有关，但 CT26 肿瘤中则没有。系统中性粒细胞耗竭消除了 Omiganan 在 TC-1 中的疗效，但进一步降低了 CT26 的生长，表明中性粒细胞在 TC-1 中对抗肿瘤作用是必需的，但在 CT26 中抑制了肿瘤控制。中性粒细胞也需要治疗性疫苗诱导的 BL/6 小鼠 RMA 肿瘤中的 T 细胞介导的控制。显然，TC-1 和 CT26 之间以及肿瘤未致敏的 BL/6 和 BALB/c 小鼠之间，循环和肿瘤内中性粒细胞在 Ly6G 和 CD62L 的表达上存在差异。RNA 测序显示，来自 BL/6 小鼠的中性粒细胞而非 BALB/c 小鼠显示出强烈的免疫激活特征，与其在 TC-1 和 RMA 与 CT26 中的相反作用相匹配。
结论
中性粒细胞的功能在小鼠品系和肿瘤类型之间存在很大差异，对肿瘤进展和治疗有影响。
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