Helfen Anne, Schnepel Annika, Rieß Jan, Stölting Miriam, Gerwing Mirjam, Masthoff Max, Vogl Thomas, Roth Johannes, Höltke Carsten, Wildgruber Moritz, Eisenblätter Michel
University Clinic of Radiology, Medical Faculty, University of Muenster and University Hospital Muenster, D-48149 Muenster, Germany.
Institute of Immunology, University of Muenster, 48149 Muenster, Germany.
Biomedicines. 2021 Jan 3;9(1):29. doi: 10.3390/biomedicines9010029.
(1) Background: The prognosis of cancer is dependent on immune cells in the tumor microenvironment (TME). The protein S100A9 is an essential regulator of the TME, associated with poor prognosis. In this study, we evaluated early therapy effects on the TME in syngeneic murine breast cancer via S100A9-specific in vivo imaging. (2) Methods: Murine 4T1 cells were implanted orthotopically in female BALB/c mice ( = 59). Tumor size-adapted fluorescence imaging was performed before and 5 days after chemo- (Doxorubicin, = 20), anti-angiogenic therapy (Bevacizumab, = 20), or placebo (NaCl, = 19). Imaging results were validated ex vivo (immunohistochemistry, flow cytometry). (3) Results: While tumor growth revealed no differences ( = 0.48), fluorescence intensities (FI) for S100A9 in Bevacizumab-treated tumors were significantly lower as compared to Doxorubicin (2.60 vs. 15.65 AU, < 0.0001). FI for Doxorubicin were significantly higher compared to placebo (8.95 AU, = 0.01). Flow cytometry revealed shifts in monocytic and T-cell cell infiltrates under therapy, correlating with imaging. (4) Conclusions: S100A9-specific imaging enables early detection of therapy effects visualizing immune cell activity in the TME, even before clinically detectable changes in tumor size. Therefore, it may serve as a non-invasive imaging biomarker for early therapy effects.
（1）背景：癌症的预后取决于肿瘤微环境（TME）中的免疫细胞。蛋白质S100A9是TME的关键调节因子，与预后不良相关。在本研究中，我们通过S100A9特异性体内成像评估了同基因小鼠乳腺癌中早期治疗对TME的影响。（2）方法：将小鼠4T1细胞原位植入雌性BALB/c小鼠体内（n = 59）。在化疗（多柔比星，n = 20）、抗血管生成治疗（贝伐单抗，n = 20）或安慰剂（氯化钠，n = 19）治疗前和治疗后5天进行肿瘤大小适应性荧光成像。成像结果通过离体验证（免疫组织化学、流式细胞术）。（3）结果：虽然肿瘤生长无差异（P = 0.48），但与多柔比星相比，贝伐单抗治疗的肿瘤中S100A9的荧光强度（FI）显著降低（2.60对15.65 AU，P < 0.0001）。多柔比星的FI与安慰剂相比显著更高（8.95 AU，P = 0.01）。流式细胞术显示治疗下单核细胞和T细胞浸润发生变化，与成像相关。（4）结论：S100A9特异性成像能够在肿瘤大小出现临床可检测变化之前，早期检测到可视化TME中免疫细胞活性的治疗效果。因此，它可作为早期治疗效果的非侵入性成像生物标志物。
