Schweihofer Verena, Bruss Christina, Seitz Stephan, Glehr Gunther, Hetterich Madeleine, Weber Florian, Hatzipanagiotou Maria, Álvarez Miriam Fernández-Pacheco, Ortmann Olaf, Brockhoff Gero, Bauer Richard J, Wege Anja Kathrin
Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany.
Bavarian Cancer Research Center (BZKF), Regensburg, Germany.
Cancer Cell Int. 2025 Mar 27;25(1):120. doi: 10.1186/s12935-025-03729-7.
The immune checkpoint targeting is nowadays an integral part of cancer therapies. However, only a minority of patients experience long-term benefits. Thus, the identification of predictive biomarkers contributing to therapy response is urgently needed.
Here, we analyzed different immune and tumor specific expression and secretion profiles in the peripheral blood and tumor samples of 50 breast cancer patients by multicolor flow cytometry and bead-based immunoassays at the time of diagnosis. Due to individual phenotype variations, we quantitatively scored 25 expressed and secreted immune-associated (e.g., LAG-3, PD-1, TIM-3, CD27) and tumor relevant markers (e.g., PD-L1, CD44, MHC-I, MHC-II) in immune checkpoint-treated triple negative breast cancer patients based on the current literature. The calculated score divided the patients into individuals with predicted pCR (total score of > 0) or predicted residual disease (total score of ≤ 0). At the end of the neoadjuvant therapy, the truly achieved pathological complete response (pCR; end of observation) was determined.
The calculated score was 79% in accordance with the achieved pCR at the time of surgery. Moreover, the sensitivity was 83.3%, the specificity 76.9%, the positive predictive value 62.5%, and the negative predictive value 90.9%. In addition, we identified a correlation of PD-1 and LAG-3 expression between tumor-associated and peripheral immune cells, which was independent of the subtype. Overall, PD-1 was the most frequently expressed checkpoint. However, in a number of patient-derived tumors, additional checkpoints as LAG-3 and TIM-3 were substantially (co-)expressed, which potentially compromises anti-PD-(L)1 mono-therapy.
This study represents a proof-of-principle to identify potential checkpoint therapy responders in advance at the time of diagnosis. The work was based on a scoring derived from a multiplexed marker profiling. However, larger patient cohorts need to be prospectively evaluated for further validation.
免疫检查点靶向治疗如今已成为癌症治疗的一个重要组成部分。然而，只有少数患者能获得长期益处。因此，迫切需要确定有助于治疗反应的预测性生物标志物。
在此，我们在诊断时通过多色流式细胞术和基于微珠的免疫测定法分析了50例乳腺癌患者外周血和肿瘤样本中不同的免疫和肿瘤特异性表达及分泌谱。由于个体表型差异，我们根据当前文献对免疫检查点治疗的三阴性乳腺癌患者中25种表达和分泌的免疫相关标志物（如LAG-3、PD-1、TIM-3、CD27）和肿瘤相关标志物（如PD-L1、CD44、MHC-I、MHC-II）进行了定量评分。计算出的分数将患者分为预测病理完全缓解（pCR；总分>0）或预测残留疾病（总分≤0）的个体。在新辅助治疗结束时，确定真正达到的病理完全缓解（pCR；观察结束）。
计算出的分数与手术时达到的pCR符合率为79%。此外，敏感性为83.3%，特异性为76.9%，阳性预测值为62.5%，阴性预测值为90.9%。此外，我们发现肿瘤相关免疫细胞和外周免疫细胞之间PD-1和LAG-3表达存在相关性，且与亚型无关。总体而言，PD-1是最常表达的检查点。然而，在许多患者来源的肿瘤中，LAG-3和TIM-3等其他检查点大量（共）表达，这可能会影响抗PD-（L）1单药治疗。
本研究为在诊断时提前识别潜在的检查点治疗反应者提供了原理验证。这项工作基于多重标志物分析得出的评分。然而，需要前瞻性评估更大规模的患者队列以进行进一步验证。
