Scholarlink

Background <p>CCR5 is a chemokine receptor involved in immune regulation and tumor progression. Its role in predicting therapy response in breast cancer remains unclear.</p> Methods <p>We evaluated CCR5 protein expression in a clinical cohort of 66 breast cancer patients treated with NAC, assessing its association with pathological complete response (pCR). Prognostic relevance was validated in the Kaplan–Meier Plotter database. We further investigated CCR5’s predictive value in a cohort receiving chemo-immunotherapy (GSE173839). Immune-related transcriptional features were assessed via GSEA and deconvolution analysis. The structural impact of the V131I CCR5 variant was explored using AlphaFold modeling, molecular dynamics simulations, and AI-based protein stability prediction.</p> Results <p>High CCR5 expression was associated with reduced pCR rates in the NAC cohort (OR = 0.06, <i>P</i> = 0.012) and with poorer RFS, particularly in HER2-negative subtypes (<i>P</i> = 0.009). In contrast, CCR5-high tumors in the chemo-immunotherapy cohort exhibited significantly higher pCR rates (OR = 2.5, <i>P</i> = 0.046), suggesting a suppressed yet immune-infiltrated microenvironment potentially responsive to immune reactivation. GSEA analysis and immune cell infiltration profiling indicate a coexistence of immune activation and immunosuppression. Structural modeling of the V131I variant suggested increased conformational flexibility and reduced stability of CCR5, implying a potential sensitivity to subtle structural perturbations.</p> Conclusion <p>Our study supports a dual regulatory hypothesis, in which CCR5 expression may influence immune dynamics and therapeutic response, while its structural stability may serve as a potential modulatory factor. This hypothesis-generating observation suggests that CCR5 could represent a potential prognostic and predictive biomarker, particularly in NAC-refractory or immune-inflamed breast cancers.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

CCR5 expression and conformational stability as potential cooperative modulators of immune phenotypes and therapy response in breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月2日

查看全文
  • En Hu,
  • Peiyu Qiu,
  • Andre Dekker,
  • Leonard Wee,
  • Chuntao Quan,
  • Deju Zhang,
  • Wenjie Liang,
  • Ni Xie

摘要

Background

CCR5 is a chemokine receptor involved in immune regulation and tumor progression. Its role in predicting therapy response in breast cancer remains unclear.

Methods

We evaluated CCR5 protein expression in a clinical cohort of 66 breast cancer patients treated with NAC, assessing its association with pathological complete response (pCR). Prognostic relevance was validated in the Kaplan–Meier Plotter database. We further investigated CCR5’s predictive value in a cohort receiving chemo-immunotherapy (GSE173839). Immune-related transcriptional features were assessed via GSEA and deconvolution analysis. The structural impact of the V131I CCR5 variant was explored using AlphaFold modeling, molecular dynamics simulations, and AI-based protein stability prediction.

Results

High CCR5 expression was associated with reduced pCR rates in the NAC cohort (OR = 0.06, P = 0.012) and with poorer RFS, particularly in HER2-negative subtypes (P = 0.009). In contrast, CCR5-high tumors in the chemo-immunotherapy cohort exhibited significantly higher pCR rates (OR = 2.5, P = 0.046), suggesting a suppressed yet immune-infiltrated microenvironment potentially responsive to immune reactivation. GSEA analysis and immune cell infiltration profiling indicate a coexistence of immune activation and immunosuppression. Structural modeling of the V131I variant suggested increased conformational flexibility and reduced stability of CCR5, implying a potential sensitivity to subtle structural perturbations.

Conclusion

Our study supports a dual regulatory hypothesis, in which CCR5 expression may influence immune dynamics and therapeutic response, while its structural stability may serve as a potential modulatory factor. This hypothesis-generating observation suggests that CCR5 could represent a potential prognostic and predictive biomarker, particularly in NAC-refractory or immune-inflamed breast cancers.