Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters.
Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters.
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DOI：
10.1158/1078-0432.ccr-16-2655
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发表时间：
2017-08-01
期刊：
影响因子：
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通讯作者：
Yates MS
中科院分区：
文献类型：
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作者：
Pakish JB;Zhang Q;Chen Z;Liang H;Chisholm GB;Yuan Y;Mok SC;Broaddus RR;Lu KH;Yates MS
最近的研究表明，与微卫星稳定型（MSS）肿瘤相比，具有高微卫星不稳定性（MSI-H）的结直肠肿瘤具有更高的免疫原性和对免疫治疗的反应。目前尚不清楚MSI-H子宫内膜癌（EC）是否也可以从这些治疗中获益。同样不清楚的是，散发性或遗传性Lynch综合征起源的MSI-H EC是否具有相同的免疫反应。多路荧光免疫组织化学（IHC）通过评估肿瘤和间质室的免疫细胞群来比较匹配的MSI-H （n=60）和MSS (n=96) EC标本。散发性MSI-H和Lynch综合征相关（LS） MSI-H EC也进行了直接比较。与MSS相比，MSI-H EC基质中免疫细胞增加，包括颗粒酶B+细胞，活化的细胞毒性T淋巴细胞（ctl， CD8+颗粒酶B+）和PD-L1+细胞。MSI-H细胞的肿瘤腔室中颗粒酶B+细胞和活化的ctl也增加。比较散发性和LS MSI-H EC显示了免疫细胞群的明显差异，表明微卫星不稳定性的机制改变了免疫反应。具体而言，与散发性MSI-H相比，LS MSI-H EC显示基质中CD8+细胞和活化的ctl增加，基质和肿瘤中的巨噬细胞减少。与LS MSI-H EC相比，散发性MSI-H EC在基质和肿瘤中增加了PD-L1+巨噬细胞。与MSS EC相比，MSI-H EC的免疫细胞浸润增加，微卫星不稳定性的遗传或散发性起源影响免疫反应。确定免疫治疗在MSI-H EC患者中的作用的临床试验必须分别评估lynch相关和散发性MSI-H肿瘤。
Recent studies show that colorectal tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy compared to microsatellite stable (MSS) tumors. It is not yet clear if MSI-H endometrial cancer (EC) may also benefit from these therapies. It is also unknown whether immune response is equivalent in MSI-H EC with sporadic or inherited Lynch syndrome origins. Multiplexed fluorescent immunohistochemistry (IHC) was used to compare matched MSI-H (n=60) and MSS (n=96) EC specimens by evaluating immune cell populations in tumor and stroma compartments. Sporadic MSI-H and Lynch syndrome-associated (LS) MSI-H EC were also directly compared. Increased immune cells were present in stroma of MSI-H EC compared to MSS, including granzyme B+ cells, activated cytotoxic T lymphocytes (CTLs, CD8+granzyme B+), and PD-L1+ cells. Granzyme B+ cells and activated CTLs were also increased in the tumor compartment of MSI-H ECs. Comparing sporadic and LS MSI-H EC showed distinct differences in immune cell populations, indicating that mechanisms underlying microsatellite instability alter immune response. Specifically, LS MSI-H EC showed increased CD8+ cells and activated CTLs in stroma, with reduced macrophages in stroma and tumor compared to sporadic MSI-H. Sporadic MSI-H had increased PD-L1+ macrophages in stroma and tumor compared to LS MSI-H EC. MSI-H EC has increased immune cell infiltration compared to MSS EC and the hereditary or sporadic origin of microsatellite instability impacts immune response. Clinical trials to determine the role of immunotherapy in patients with MSI-H EC must evaluate Lynch-related and sporadic MSI-H tumors separately.