PO.TB10.19 · 肿瘤生物学

化疗初治三阴性乳腺癌中MHC I类表达及多种免疫细胞的分布：抗原提呈的缺失可带来高TILs和良好预后，可能通过调节性T细胞构成的减少实现

MHC class 1 expression and distribution of multiple immune cells in chemotherapy-naïve triple-negative breast cancers: lack of antigen-presentation can bring high TILs and good prognosis, possibly via decreased regulatory T-cell composition

编号 4978 展板 3 时间 4/21 09:00–12:00 区域 Section 32 主讲 Makiko Yamashita, PhD

分会场 Tumor-Immune Crosstalk

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作者与单位 Authors & Affiliations

Makiko Yamashita¹, Akira I. Hida², Naomi Gondo³, Yasuyo Ohi⁴, Shigehisa Kitano¹

¹Department of Advanced Medical Development, Cancer Institute Hospital, Tokyo, Japan,²Department of Pathology, Matsuyama Shimin Hospital, Ehime, Japan,³Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan,⁴Department of Pathology, Sagara Hospital, Kagoshima, Japan

摘要 Abstract

中文摘要

三阴性乳腺癌（TNBCs）因ER、PgR和HER2均为阴性，一直未成为靶向治疗的候选对象。此外，TNBCs的侵袭性使其治疗充满挑战。然而，近期进展包括免疫检查点抑制剂（ICIs），其对某些TNBCs有效。癌症微环境中肿瘤浸润淋巴细胞（TILs）的丰度与更好的预后，以及化疗和ICIs疗效的提升相关。我们尚不清楚究竟是什么造成了TIL高或低的差异，并希望研究癌症免疫循环。我们回顾性纳入了来自单一机构的153例连续TNBC患者，所有患者均接受了根治性初次手术和标准辅助化疗。具有代表性的手术样本经免疫组化染色检测MHC I类，由一名病理医生按3分（弥漫阳性）到0分（几乎阴性）评分。异质性染色评为2分（阳性区域>50%）或1分（阳性区域<50%）。TILs在苏木精和伊红染色后进行评估，并记录无复发生存。对30例具有不同MHC表达水平的病例，采用多重荧光技术染色CD3、CD4、CD8、CD20、CD56、CD204、FoxP3和全角蛋白（pan-cytokeratin）。选取600个小型感兴趣区域，并根据肿瘤MHC（阳性/阴性）和间质TILs（高/低）归入四类之一。在图像上计算染色信号，并进行聚类以确定细胞在肿瘤或间质区域中的分布。 TIL丰度是一个独立的预后因素（HR：2.52，p=0.013）。MHC I类表达在许多病例中为弥漫阳性（153例中有88例评为3分），四例为阴性（0分）。MHC阳性与更高的TILs相关；然而，MHC评分为0分的四例却具有高TILs（平均42.5%），且在平均14.5年的随访期内未出现复发或死亡。高TIL区域免疫细胞的详细构成显示存在大量CD3+和CD20+细胞浸润，而CD204+细胞在低TIL区域数量众多。MHC I类阴性区域的FoxP3+细胞比阳性区域更少，即使在高TIL区域也是如此。MHC阳性与阴性区域之间CD56+细胞数量无显著差异。免疫细胞的聚类分析显示CD204是该群体的主要划分因素。 MHC I类阴性的TNBCs含有相对较高的TILs，其主要成分为CD3+和CD20+细胞。FoxP3+细胞的存在似乎需要MHC I类，而FoxP3负性调节的缺失可能导致了高TIL和更好的预后。我们的发现指出抗原提呈与T细胞募集之间存在一个缺失的环节。

查看英文原文 English abstract

Triple-negative breast cancers (TNBCs) have not been candidates for targeted therapies because they are negative for ER, PgR, and HER2. In addition, the aggressive nature of TNBCs makes their treatment challenging. However, recent advances include immune checkpoint inhibitors (ICIs), which are effective against some TNBCs. The abundance of tumor-infiltrating lymphocytes (TILs) in the cancer microenvironment correlates with better prognosis, and improved efficacy of chemotherapy and ICIs. We don't know yet in detail what makes the difference, high or low TIL, and wanted to investigate cancer immunity cycles. We retrospectively recruited 153 consecutive TNBC patients from a single institution, all of whom had primary curative surgery and standard adjuvant chemotherapy. Representative surgical samples were immunohistochemically stained for MHC class 1 and evaluated by a pathologist in a score of 3 (diffusely positive) to 0 (almost negative). Heterogeneous staining was scored as 2 (positive area>50%) or 1 (positive area<50%). TILs were estimated after hematoxylin & eosin staining, and relapse-free survival was recorded. Thirty cases with different levels of MHC expression were stained for CD3, CD4, CD8, CD20, CD56, CD204, FoxP3, and pan-cytokeratin using a multi-fluorescence technique. Six-hundred small areas of interest were selected and assigned to one of four categories according to tumoral MHC (positive/negative) and stromal TILs (high/low). Staining signals were calculated on the images, and clustered to determine the distribution of cells in areas of tumor or stroma. TIL abundance was an independent prognostic factor (HR: 2.52, p =0.013). MHC class 1 expression was diffusely positive in many cases (score 3 in 88 of 153 cases), and four cases were negative (score 0). MHC positivity correlated with higher TILs; nevertheless, the four cases with an MHC score of 0 had high TILs (42.5% on average) and showed no recurrence or death during the mean follow-up period of 14.5 years. Detailed composition of immune cells in areas of high TIL showed infiltration by many CD3+ and CD20+ cells, while CD204+ cells were numerous in areas of low TIL. MHC class 1-negative areas had fewer FoxP3+ cells than positive areas, even in areas of high TIL. There was no significant difference in CD56+ cell number between MHC-positive and -negative areas. Cluster analysis of immune cells revealed CD204 to be a major divider of the population. MHC class 1-negative TNBCs contained relatively high TILs, the main components of which were CD3+ and CD20+ cells. The presence of FoxP3+ cells seems to require HMC class 1, and the lack of negative regulation by FoxP3 might have resulted in high TIL and better prognosis. Our findings indicate a missing link between antigen presentation and T-cell recruitment.

利益披露 Disclosure

M. Yamashita, None. A. I. Hida, Visiopharm ). Medmain ). Daiichi Sankyo lecture fee. N. Gondo, None.. Y. Ohi, None. S. Kitano, Astra Zeneca ), lecture fee. Boehringer Ingelheim ), lecture fee. Bristol-Myers Squibb lecture fee. Chugai ), lecture fee. Daiichii Sankyo ), lecture fee. Eisai ), lecture fee. LOXO Oncology ). Merck ), lecture fee. MSD ), lecture fee. Moderna ). Takeda ), lecture fee. Rakuten Medical Advisory Board. Kyowa Kirin ), Advisory Board. Ono Pharmaceutical Co., Ltd ), Scientific adviser, Lecture fee. United Immunity Advisory Board. Abbvie ). Astellas ). Eli Lilly ). GlaxoSmithKline ). Incyte ).

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