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

 Carlos R. Gil Del Alcazar  ;  Sung Jin Huh  ;  Muhammad B. Ekram  ;  Anne Trinh  ;  Lin L. Liu  ;  Francisco Beca  ;  Xiaoyuan Zi  ;  Minsuk Kwak  ;  Helga Bergholtz  ;  Ying Su  ;  Lina Ding  ;  Hege G. Russnes  ;  Andrea L. Richardson  ;  Kirsten Babski  ;  Elizabeth Min Hui Kim  ;  Charles H. McDonnell III  ;  Jon Wagner  ;  Ron Rowberry  ;  Gordon J. Freeman  ;  Deborah Dillon  ;  Therese Sorlie  ;  Lisa M. Coussens  ;  Judy E. Garber  ;  Rong Fan  ;  Kristie Bobolis  ;  D. Craig Allred  ;  Joon Jeong  ;  So Yeon Park  ;  Franziska Michor  ;  Kornelia Polyak 
 CANCER DISCOVERY, Vol.7(10) : 1098-1115, 2017 
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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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
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