Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
Biochemistry Center (BZH), University of Heidelberg, Heidelberg, Germany.
Int J Cancer. 2019 Nov 1;145(9):2509-2520. doi: 10.1002/ijc.32378. Epub 2019 May 13.
The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.
免疫微环境在支持肿瘤生长和转移中起着至关重要的作用。肿瘤相关巨噬细胞（TAMs）和中性粒细胞（TANs）是这种微环境的重要组成部分，几乎影响所有实体瘤的肿瘤生长和进展。此外，研究发现 TAMs、TANs 和肿瘤浸润树突状细胞（TIDCs）浸润到特定的远处器官，为转移性细胞播种做准备，形成前转移龛。脾脏被认为是循环和肿瘤浸润免疫细胞的主要储存库和来源。然而，关于其在支持肿瘤生长中的作用存在差异。因此，我们在这里研究了脾切除术在原发性肿瘤和转移性生长以及炎症龛形成中的作用。在小鼠 4T1 和 E0771 乳腺癌和 Panc02 胰腺癌模型中，我们的结果表明，虽然脾切除术减少了原发性肿瘤内浸润的 TAMs、TANs 和 TIDCs 的数量，但并不影响其生长。与此一致，脾切除术后，转移微环境中 TAMs、TANs 和 TIDCs 的积累减少。然而，有趣的是，这取决于转移途径/部位而影响转移生长。脾切除术后，乳腺癌血源性肺转移的数量减少，但在乳腺癌或胰腺淋巴结转移中没有观察到这种影响。此外，我们观察到携带乳腺癌的小鼠肺部前转移龛的免疫组成发生改变，这可能导致转移减少。总之，我们的研究结果表明，脾切除术不仅影响原发性肿瘤的免疫微环境，还影响前转移和转移部位的免疫微环境。
