pH响应聚合物胶束重塑PIK3CA突变Luminal型乳腺癌免疫微环境

pH-responsive polymer micelles reshape the immune microenvironment ofPIK3CA-mutated Luminal breast cancer

    摘要
  • 摘要:
    目的 探讨PIK3CA突变对Luminal型乳腺癌免疫微环境的影响，以及pH响应性聚合物胶束依赖的药物靶向递送重塑PIK3CA突变Luminal型乳腺癌肿瘤免疫微环境的作用。
    方法 采用生物信息学分析PIK3CA在乳腺癌中的突变特点；构建PIK3CA突变的Luminal型乳腺癌小鼠移植瘤模型，通过单细胞质谱流式技术（mass cytometry，CyTOF）探究肿瘤免疫微环境的变化；收集2004年8月至2008年12月天津医科大学肿瘤医院62例Luminal型乳腺癌患者（BRCA cohort）组织样本，在组织水平探索PIK3CA突变与肿瘤免疫微环境的关系；负载Alpelisib的pH响应性聚合物胶束（Alpelisib@MSPM）的制备和表征鉴定；动物实验探究Alpelisib@MSPM对PIK3CA突变Luminal型乳腺癌的治疗效果。
    结果 PIK3CA是乳腺癌中最常见的突变基因之一，尤其在Luminal型乳腺癌中，其突变频率最高；通过CyTOF分析发现在PIK3CA突变乳腺癌移植瘤中PIK3CA突变可以驱动肿瘤免疫抑制微环境的形成；多重荧光免疫组织化学分析发现PIK3CA突变显著影响乳腺癌免疫微环境，呈现骨髓来源抑制细胞（myeloid-derived suppressor cells，MDSCs）高浸润和CD8+T细胞低浸润现象；成功制备负载Alpelisib的pH响应性聚合物胶束，胶束的平均粒径约127 nm；经Alpelisib和Alpelisib@MSPM治疗后，PIK3CA突变的Luminal型乳腺癌小鼠肿瘤生长缓慢，肿瘤免疫微环境中MDSCs的比例明显降低，CD8+T细胞的比例显著升高，并且在Alpelisib@MSPM 组中治疗效果更加显著。
    结论 PIK3CA突变驱动Luminal型乳腺癌免疫抑制微环境的形成，pH响应性聚合物胶束依赖的Alpelisib靶向递送能够显著增强乳腺癌的治疗效果。

     

    Abstract:
    Objective To investigate the effect of PIK3CA mutations on the tumor immune microenvironment in Luminal breast cancer and evaluate the potential of Alpelisib-loaded pH-responsive polymer micelles in modulating the tumor immune microenvironment.
    Methods PIK3CA mutations in breast cancer were analyzed using bioinformatics tools. A mouse xenograft model of Luminal breast cancer harboring a PIK3CA mutation was established, and alterations in the tumor immune microenvironment were examined using mass cytometry (CyTOF). During the period from August 2004 to December 2008 in Tianjin Medical University Cancer Hospital, tissue biopsies of 62 Luminal breast cancer patients in the BRCA cohort were collected Study the relationship between PIK3CA mutations and tumor immune microenvironment at the organizational level. Alpelisib-loaded polymer micelles (Alpelisib@MSPM) were synthesized, characterized, and evaluated for therapeutic efficacy in Luminal breast cancer with PIK3CA mutations.
    Results PIK3CA is one of the most frequently mutated genes in breast cancer, with the highest prevalence in Luminal subtypes. CyTOF analysis demonstrated that PIK3CA mutations contribute to a tumor immunosuppressive microenvironment in xenografts. Multiplex fluorescence immunohistochemistry revealed that PIK3CA-mutated tumors exhibited more infiltration of myeloid-derived suppressor cells (MDSCs) and less infiltration of CD8⁺ T cells. The synthesized Alpelisib-loaded pH-responsive polymer micelles had an average size of approximately 127 nm. Treatment with Alpelisib and Alpelisib@MSPM reduced tumor growth in mice with PIK3CA-mutated Luminal breast cancer. Notably, the proportion of MDSCs decreased, whereas CD8⁺ T cell infiltration increased significantly, with the more pronounced effect observed in the Alpelisib@MSPM treatment group.
    Conclusions PIK3CA mutations drive the formation of a tumor immunosuppressive microenvironment in Luminal breast cancer. Targeted Alpelisib delivery via pH-responsive polymer micelles significantly enhances therapeutic efficacy in PIK3CA-mutated breast cancer.

     

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