Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition,Cancer Discovery

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Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition
Cancer Discovery ( IF 28.2 ) Pub Date : 2017-01-01 , DOI: 10.1158/2159-8290.cd-17-0222
Carlos R Gil Del Alcazar _{1,

2,

3} , Sung Jin Huh _{1,

2,

3} , Muhammad B Ekram _{1,

2,

3} , Anne Trinh _{1,

2,

3} , Lin L Liu _{4,

5} , Francisco Beca _{1,

2,

3} , Xiaoyuan Zi _{6,

7} , Minsuk Kwak ₆ , Helga Bergholtz ₈ , Ying Su _{1,

2,

3} , Lina Ding _{1,

2,

3} , Hege G Russnes ₈ , Andrea L Richardson _{9,

10,

11} , Kirsten Babski ₁₂ , Elizabeth Min Hui Kim ₁₂ , Charles H McDonnell ₁₂ , Jon Wagner ₁₂ , Ron Rowberry ₁₂ , Gordon J Freeman _{1,

3} , Deborah Dillon _{10,

11} , Therese Sorlie ₈ , Lisa M Coussens ₁₃ , Judy E Garber _{1,

2,

3} , Rong Fan ₆ , Kristie Bobolis ₁₂ , D Craig Allred ₁₄ , Joon Jeong ₁₅ , So Yeon Park ₁₆ , Franziska Michor _{4,

5} , Kornelia Polyak _{1,

2,

3,

17,

18}

Affiliation

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
Second Military Medical University, Shanghai, P.R. China.
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Pathology, Harvard Medical School, Boston, Massachusetts.
Sutter Roseville Medical Center, Roseville, California.
Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri.
Department of Surgery, Gangnam Severance Hospital, Yonsei University Medical College, Seoul, Korea.
Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
The Broad Institute, Cambridge, Massachusetts.
Harvard Stem Cell Institute, Cambridge, Massachusetts.

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45⁺CD3⁺ T cells demonstrated a decrease in CD8⁺ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB⁺CD8⁺ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2⁺ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.

SIGNIFICANCE: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1–18. ©2017 AACR.

See related commentary by Speiser and Verdeil, p. 1062.

中文翻译：

乳腺癌原位癌向侵袭性癌转变过程中的免疫逃逸

为了研究乳腺肿瘤进展过程中的免疫逃逸，我们分析了正常乳腺组织、导管原位癌（DCIS）和浸润性导管癌（IDC）中的白细胞组成。我们发现多种细胞类型（包括 T 细胞和中性粒细胞）存在显着的组织和肿瘤亚型特异性差异。^{CD45 +} CD3 ⁺ T 细胞的基因表达谱表明 IDC 中 CD8 ⁺特征减少。免疫荧光分析显示，IDC 中活化的 GZMB ⁺ CD8 ⁺ T 细胞少于 DCIS，包括匹配的 DCIS 和复发性 IDC。DCIS 中的 T 细胞受体克隆型多样性显着高于 IDC。表达免疫检查点蛋白 TIGIT 的 T 细胞在 DCIS 中更为常见，而高 PD-L1 表达和CD274（编码 PD-L1）扩增仅在三阴性 IDC 中检测到。17q12 趋化因子簇与ERBB2的共扩增将 HER2 ⁺乳腺肿瘤细分为免疫学和临床上不同的亚型。我们的结果显示肿瘤进展过程中癌细胞和免疫微环境的共同进化。