The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis
The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis
复制标题
DOI：
10.1126/scitranslmed.aad6352
复制
发表时间：
2016-02-24
影响因子：
17.1
通讯作者：
Galon, Jerome
中科院分区：
文献类型：
--
作者：
Mlecnik, Bernhard;Bindea, Gabriela;Galon, Jerome
虽然远处转移是癌症患者死亡的主要原因，但关于促进或抑制转移的机制的基本问题仍未得到解答。我们展示了突变、基因组不稳定、淋巴管和血管形成以及肿瘤微环境的免疫环境对大量结直肠癌患者同步转移的影响。我们观察到原发肿瘤之间有很大的遗传异质性，但在染色体不稳定或关键的癌症相关突变方面没有重大差异。癌症相关基因的表达水平在患者之间也观察到了相似的模式。未发现与M期相关的肿瘤相关基因或途径。相反，FBXW7的突变与无转移相关，并与T细胞增殖和抗原提呈功能的表达增加相关。分析肿瘤微环境，我们观察到转移过程的两个特征：淋巴管的存在减少和免疫细胞毒性降低。这些事件可能是导致同时性和异时性转移的始动因素。我们的数据显示了免疫核心、细胞毒性免疫特征和边缘淋巴管的增加对远处转移的产生的保护作用，而不考虑基因组的不稳定性。
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.