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

• Published in: Cancer discovery 2017-10, Vol.7 (10), p.1098-1115
• Main Authors: Gil Del Alcazar, Carlos R, Huh, Sung Jin, Ekram, Muhammad B, Trinh, Anne, Liu, Lin L, Beca, Francisco, Zi, Xiaoyuan, Kwak, Minsuk, Bergholtz, Helga, Su, Ying, Ding, Lina, Russnes, Hege G, Richardson, Andrea L, Babski, Kirsten, Min Hui Kim, Elizabeth, McDonnell, 3rd, Charles H, Wagner, Jon, Rowberry, Ron, Freeman, Gordon J, Dillon, Deborah, Sorlie, Therese, Coussens, Lisa M, Garber, Judy E, Fan, Rong, Bobolis, Kristie, Allred, D Craig, Jeong, Joon, Park, So Yeon, Michor, Franziska, Polyak, Kornelia
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - genetics; Biomarkers, Tumor - genetics; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - immunology; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - immunology; CD3 Complex - genetics; Disease Progression; Female; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Humans; Leukocyte Common Antigens - genetics; Receptor, ErbB-2 - genetics; T-Lymphocytes - immunology; Tumor Microenvironment
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-17-0222

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma (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 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with subdivided HER2 breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. 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 to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. .