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, Jon Wagner, Ron Rowberry, Gordon J. Freeman, Deborah Dillon & 10 others Therese Sorlie, Lisa M. Coussens, Judy E. Garber, Rong Fan, Kristie Bobolis, D. Craig Allred, Jeong Joon, So Yeon Park, Franziska Michor, Kornelia Polyak

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 signifi cant tissue and tumor subtype-specifi c differences in multiple cell types including T cells and neutrophils. Gene expression profi ling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofl uorescence 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 signifi cantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplifi cation of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplifi cation 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.

Original languageEnglish
Pages (from-to)1098-1115
Number of pages18
JournalCancer Discovery
Volume7
Issue number10
DOIs
Publication statusPublished - 2017 Oct 1

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Carcinoma, Intraductal, Noninfiltrating
Breast Neoplasms
Carcinoma
Ductal Carcinoma
T-Lymphocytes
Neoplasms
Cations
Tumor Escape
Cellular Microenvironment
T-Cell Antigen Receptor
Chemokines
Immunotherapy
Breast
Neutrophils
Leukocytes
Gene Expression
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Gil Del Alcazar, C. R., Huh, S. J., Ekram, M. B., Trinh, A., Liu, L. L., Beca, F., ... Polyak, K. (2017). Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discovery, 7(10), 1098-1115. https://doi.org/10.1158/2159-8290.CD-17-0222
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 ; Kim, Elizabeth Min Hui ; McDonnell, 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 ; Joon, Jeong ; Park, So Yeon ; Michor, Franziska ; Polyak, Kornelia. / Immune escape in breast cancer during in situ to invasive carcinoma transition. In: Cancer Discovery. 2017 ; Vol. 7, No. 10. pp. 1098-1115.
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abstract = "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 signifi cant tissue and tumor subtype-specifi c differences in multiple cell types including T cells and neutrophils. Gene expression profi ling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofl uorescence 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 signifi cantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplifi cation of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplifi cation 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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Gil Del Alcazar, CR, Huh, SJ, Ekram, MB, Trinh, A, Liu, LL, Beca, F, Zi, X, Kwak, M, Bergholtz, H, Su, Y, Ding, L, Russnes, HG, Richardson, AL, Babski, K, Kim, EMH, McDonnell, CH, Wagner, J, Rowberry, R, Freeman, GJ, Dillon, D, Sorlie, T, Coussens, LM, Garber, JE, Fan, R, Bobolis, K, Allred, DC, Joon, J, Park, SY, Michor, F & Polyak, K 2017, 'Immune escape in breast cancer during in situ to invasive carcinoma transition', Cancer Discovery, vol. 7, no. 10, pp. 1098-1115. https://doi.org/10.1158/2159-8290.CD-17-0222

Immune escape in breast cancer during in situ to invasive carcinoma transition. / 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; Kim, Elizabeth Min Hui; McDonnell, 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; Joon, Jeong; Park, So Yeon; Michor, Franziska; Polyak, Kornelia.

In: Cancer Discovery, Vol. 7, No. 10, 01.10.2017, p. 1098-1115.

Research output: Contribution to journalArticle

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T1 - Immune escape in breast cancer during in situ to invasive carcinoma transition

AU - Gil Del Alcazar, Carlos R.

AU - Huh, Sung Jin

AU - Ekram, Muhammad B.

AU - Trinh, Anne

AU - Liu, Lin L.

AU - Beca, Francisco

AU - Zi, Xiaoyuan

AU - Kwak, Minsuk

AU - Bergholtz, Helga

AU - Su, Ying

AU - Ding, Lina

AU - Russnes, Hege G.

AU - Richardson, Andrea L.

AU - Babski, Kirsten

AU - Kim, Elizabeth Min Hui

AU - McDonnell, Charles H.

AU - Wagner, Jon

AU - Rowberry, Ron

AU - Freeman, Gordon J.

AU - Dillon, Deborah

AU - Sorlie, Therese

AU - Coussens, Lisa M.

AU - Garber, Judy E.

AU - Fan, Rong

AU - Bobolis, Kristie

AU - Allred, D. Craig

AU - Joon, Jeong

AU - Park, So Yeon

AU - Michor, Franziska

AU - Polyak, Kornelia

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N2 - 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 signifi cant tissue and tumor subtype-specifi c differences in multiple cell types including T cells and neutrophils. Gene expression profi ling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofl uorescence 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 signifi cantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplifi cation of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplifi cation 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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Gil Del Alcazar CR, Huh SJ, Ekram MB, Trinh A, Liu LL, Beca F et al. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discovery. 2017 Oct 1;7(10):1098-1115. https://doi.org/10.1158/2159-8290.CD-17-0222