Heimer Maurice M, Cimic Amra, Kloiber-Langhorst Sandra, Antons Melissa J, Stueckl Jennifer, Hirner-Eppeneder Heidrun, Kunz Wolfgang G, Dietrich Olaf, Ricke Jens, Herr Felix L, Cyran Clemens C
Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
Eur Radiol Exp. 2025 Jun 14;9(1):59. doi: 10.1186/s41747-025-00597-8.
BACKGROUND: We assessed immunotherapy response in a murine melanoma model using multiparametric magnetic resonance imaging (mpMRI) features with ex vivo immunohistochemical validation. METHODS: Murine melanoma cells (B16-F10) were inoculated into the subcutaneous flank of n = 28 C57BL/6 mice (n = 14 therapy; n = 14 control). Baseline mpMRI was acquired on day 7 at 3 T. The immunotherapy group received three intraperitoneal injections of anti-PD-L1 and anti-CTLA-4 antibodies on days 7, 9, and 11 after inoculation. Controls received a volume equivalent placebo. Follow-up mpMRI was performed on day 12. We assessed tumor volume, diffusion-weighted imaging parameters, including the apparent diffusion coefficient (ADC), and dynamic-contrast-enhanced metrics, including plasma volume and plasma flow. Tumor-infiltrating lymphocytes (TIL; CD8+), cell proliferation (Ki-67), apoptosis (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling, TUNEL), and microvascular density (CD31+) were assessed in a validation cohort of n = 24 animals for time-matched ex vivo validation. RESULTS: An increase in tumor volume was observed in both groups (p ≤ 0.004) without difference at follow-up (p = 0.630). A lower ADC value was observed in the immunotherapy group at follow-up (p = 0.001). Immunohistochemistry revealed higher TUNEL values (p < 0.001) and CD8+ TILs (p = 0.048) following immunotherapy, as well as lower tumor cell Ki-67 values (p < 0.001) and microvascular density/CD31+ (p < 0.001). CONCLUSION: Lower tumor ADC, paired with higher intratumoral expression of CD8+ TIL, was observed five days after immunotherapy, suggestive of early immunological response. Ex vivo immunohistochemistry confirmed the antitumoral efficacy of immunotherapy. RELEVANCE STATEMENT: Compared to tumor size, diffusion-weighted MRI demonstrated potential for early response assessment to immunotherapy in a murine melanoma model, which could reflect changes in the tumor microenvironment and immune cell infiltration. KEY POINTS: No difference in tumor volume was observed between groups before and after therapy. Lower ADC values paired with increased CD8+ TILs were observed following immunotherapy. Ex vivo immunohistochemistry confirmed antitumoral efficacy of anti-PD-L1 and anti-CTLA-4 immunotherapy.
背景：我们使用多参数磁共振成像（mpMRI）特征并结合体外免疫组化验证，在小鼠黑色素瘤模型中评估免疫治疗反应。 方法：将小鼠黑色素瘤细胞（B16-F10）接种到n = 28只C57BL/6小鼠的侧腹皮下（n = 14只接受治疗；n = 14只作为对照）。在第7天于3T条件下采集基线mpMRI。免疫治疗组在接种后第7、9和11天接受三次腹腔注射抗PD-L1和抗CTLA-4抗体。对照组接受等量体积的安慰剂。在第12天进行随访mpMRI。我们评估了肿瘤体积、扩散加权成像参数，包括表观扩散系数（ADC），以及动态对比增强指标，包括血容量和血流量。在n = 24只动物的验证队列中评估肿瘤浸润淋巴细胞（TIL；CD8+）、细胞增殖（Ki-67）、凋亡（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记，TUNEL）和微血管密度（CD31+），以进行时间匹配的体外验证。 结果：两组均观察到肿瘤体积增加（p≤0.004），随访时无差异（p = 0.630）。免疫治疗组在随访时观察到较低的ADC值（p = 0.001）。免疫组化显示免疫治疗后TUNEL值较高（p < 0.001）和CD8+ TILs较高（p = 0.048），以及肿瘤细胞Ki-67值较低（p < 0.001）和微血管密度/CD31+较低（p < 0.001）。 结论：免疫治疗五天后观察到肿瘤ADC降低，同时肿瘤内CD8+ TIL表达升高，提示早期免疫反应。体外免疫组化证实了免疫治疗的抗肿瘤疗效。 相关性声明：与肿瘤大小相比，扩散加权MRI显示在小鼠黑色素瘤模型中对免疫治疗早期反应评估具有潜力，这可以反映肿瘤微环境和免疫细胞浸润的变化。 关键点：治疗前后两组肿瘤体积无差异。免疫治疗后观察到较低的ADC值与增加的CD8+ TILs。体外免疫组化证实抗PD-L1和抗CTLA-4免疫治疗的抗肿瘤疗效。
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