器官特异性免疫设定点是乳腺癌转移部位不同免疫特征的基础。
Organ-specific immune setpoints underlie divergent immune profiles across metastatic sites in breast cancer.
发表日期:2024 Jul 25
作者:
Colt A Egelston, Weihua Guo, Diana L Simons, Jian Ye, Christian Avalos, Shawn T Solomon, Mary Nwangwu, Michael S Nelson, Jiayi Tan, Eliza R Bacon, Kena Ihle, Daniel Schmolze, Lusine Tumyan, James R Waisman, Peter P Lee
来源:
Cancer Immunology Research
摘要:
肿瘤微环境 (TME) 内的免疫成分在癌症转移和对治疗反应的倾向中发挥着核心作用。先前的研究表明,转移性 TME 受到免疫抑制。然而,患者体内多个转移部位的可及性有限,使得在多器官转移的情况下评估免疫 TME 变得困难。我们利用快速死后组织收集方案来评估乳腺癌转移的多个部位和配对的无肿瘤组织中的免疫组成。发现转移瘤与相同器官类型的配对无肿瘤组织具有相当的免疫细胞密度和组成。相比之下,不同器官类型的转移组织和无肿瘤组织中的免疫细胞密度存在显着差异,肺部免疫浸润始终大于肝脏。这些免疫分析结果在流式细胞术和基于多重免疫荧光的空间分析之间是一致的。此外,我们发现粒细胞是肺和肝转移中主要的肿瘤浸润免疫细胞,并且这些粒细胞构成了许多组织部位中表达 PD-L1 的细胞的大部分。我们还发现了肺和肝转移中免疫抑制的不同潜在机制,肺中 PD-L1 抗原呈递细胞的表达增加,肝脏中激活的调节性 T 细胞和 HLA-DRlow 单核细胞的数量更高。这些结果共同表明,转移的免疫环境是由器官类型决定的,并且免疫治疗策略可能受益于针对免疫 TME 的组织特异性特征的独特定制。
Immune composition within the tumor microenvironment (TME) plays a central role in the propensity of cancer to metastasize and to respond to therapy. Previous studies suggested that the metastatic TME is immune suppressed. However, limited accessibility to multiple metastatic sites within patients has made assessment of the immune TME in the context of multi-organ metastases difficult. We utilized a rapid postmortem tissue collection protocol to assess immune composition in numerous sites of breast cancer metastasis and paired tumor-free tissues. Metastases were found to have comparable immune cell densities and composition to paired tumor-free tissues of the same organ type. In contrast, immune cell densities in both metastatic and tumor-free tissues were significantly different between organ types, with lung immune infiltration consistently greater than liver. These immune profiling results were consistent between both flow cytometry and multiplex immunofluorescence-based spatial analysis. Furthermore, we found granulocytes were a predominant tumor-infiltrating immune cell in both lung and liver metastases and these granulocytes made up the majority of PD-L1-expressing cells in many tissue sites. We also identified distinct potential mechanisms of immunosuppression in lung and liver metastases, with lung having increased expression of PD-L1+ antigen-presenting cells and liver having higher numbers of activated regulatory T cells and HLA-DRlow monocytes. Together these results demonstrate that immune contexture of metastases is dictated by organ type, and that immunotherapy strategies may benefit from unique tailoring to tissue-specific features of the immune TME.