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Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness Lance D Published OnlineFirst April 28, 2016; DOI: 10.1158/2326-6066.CIR-15-0149 Research Article Cancer Immunology Research Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness Lance D. Miller1,2, Jeff A. Chou3, Michael A. Black4, Cristin Print5, Julia Chifman1, Angela Alistar2,6, Thomas Putti7, Xiaobo Zhou8, Davide Bedognetti9, Wouter Hendrickx9, Ashok Pullikuth1, Jonathan Rennhack10, Eran R. Andrechek10, Sandra Demaria11, Ena Wang9, and Francesco M. Marincola12 Abstract The abundance and functional orientation of tumor-infiltrat- mostly of highly proliferative tumors of the basal-like, HER2- ing lymphocytes in breast cancer is associated with distant metas- enriched, and luminal B subtypes, could be stratified by the tasis-free survival, yet how this association is influenced by tumor immune classifier into significantly different prognostic groups, phenotypic heterogeneity is poorly understood. Here, a bioinfor- while IBD tumors could not, indicating the potential for produc- matics approach defined tumor biologic attributes that influence tive engagement of metastasis-protective immunity in IBE tumors, this association and delineated tumor subtypes that may differ in but not in IBD tumors. The prognostic stratification in IBE was their ability to sustain durable antitumor immune responses. A independent of conventional variables. Gene network analysis large database of breast tumor expression profiles and associated predicted the activation of TNFa/IFNg signaling pathways in IBE clinical data was compiled, from which the ability of phenotypic tumors and the activation of the transforming growth factor-b markers to significantly influence the prognostic performance of a pathway in IBD tumors. This prediction supports a model in classification model that incorporates immune cell–specific gene which breast tumors can be distinguished on the basis of their signatures was ascertained. Markers of cell proliferation and potential for metastasis-protective immune responsiveness. intrinsic molecular subtype reproducibly distinguished two breast Whether IBE and IBD represent clinically relevant contexts for cancer subtypes that we refer to as immune benefit-enabled (IBE) evaluating sensitivity to immunotherapeutic agents warrants fur- and immune benefit-disabled (IBD). The IBE tumors, comprised ther investigation. Cancer Immunol Res; 4(7); 600–10. Ó2016 AACR. Introduction 1Department of Cancer Biology, Wake Forest School of Medicine, As cancer cells emerge and propagate, they must acquire evasive Winston-Salem, North Carolina. 2The Comprehensive Cancer Center tactics to escape immune destruction. These tactics must endow 3 of Wake Forest University, Winston Salem, North Carolina. Depart- malignant cells with the ability to avoid elimination by the ment of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina. 4Department of Biochemistry, Otago immune system early in their formation, establish equilibrium School of Medical Sciences, University of Otago, Dunedin, New Zeal- with the immune system as the tumor grows, and eventually 5 and. Department of Molecular Medicine and Pathology and Maurice escape from immune control, enabling tumor progression (1). Wilkins Institute, Faculty of Medical and Health Sciences, The Univer- sity of Auckland, Auckland, New Zealand. 6Department of Internal However, results from both mechanistic and correlative studies Medicine, Wake Forest School of Medicine, Winston-Salem, North indicate that some established tumors, with or without therapeu- 7 Carolina. Department of Pathology,Yong Loo Lin School of Medicine, tic intervention, can eventually succumb to immune control by National University of Singapore, National University Hospital, Singa- – pore. 8Department of Radiology, Center for Bioinformatics and Sys- establishment of a helper T-cell type 1 (Th1) type immune tems Biology,Wake Forest School of Medicine,Winston-Salem, North response that mediates tumor rejection and gives rise to immu- Carolina. 9Division of Translational Medicine, Sidra Medical and nologic memory that guards against future metastases (2–4). Research Center, Doha, Qatar. 10Department of Physiology, Michigan State University, East Lansing, Michigan. 11Department of Radiation Consistent with these observations, numerous histologic studies Oncology and Pathology, Weill Cornell Medical College, New York, have demonstrated that the abundance and functional orienta- New York. 12Office of the Chief Research Officer, Research Branch, tion of tumor-infiltrating effector cells within primary tumors can Sidra Medical and Research Center, Doha, Qatar. significantly predict recurrence-free survival of patients with can- Note: Supplementary data for this article are available at Cancer Immunology cer (5). This is particularly true of cancers of the breast, colon, Research Online (http://cancerimmunolres.aacrjournals.org/). ovary, lung, liver, head/neck, skin, and brain, whereby abundant Corresponding Author: Lance David Miller, Wake Forest Baptist Health, tumor-infiltrating lymphocytes (TIL), namely cytotoxic T cells School of Medicine, Department of Cancer Biology, Medical Center Boule- (CTL), memory T cells, natural killer (NK) cells, and NKT cells, vard,Winston-Salem,NC27157.Phone: 336-716-6017; Fax: 336-716-0255; have been associated with the suppression of metastatic recur- E-mail: [email protected] rence (5–7). Together, these findings suggest that (i) abundant doi: 10.1158/2326-6066.CIR-15-0149 tumor infiltration by effector cells is indicative of an antitumor Ó2016 American Association for Cancer Research. immune response, and (ii) the induction of tumor-reactive 600 Cancer Immunol Res; 4(7) July 2016 Downloaded from cancerimmunolres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 28, 2016; DOI: 10.1158/2326-6066.CIR-15-0149 Immunogenic Subtypes of Breast Cancer immunity capable of guarding against metastatic progression is a respectively) could not be stratified by the immune metagenes fairly common event in multiple cancer types. into significantly different survival groups. Intriguingly, these Microarray tumor profiling studies are now providing compel- observations suggest that the successful recognition and elimina- ling evidence that the relative abundance of tumor-infiltrating tion of breast cancer by the immune system may be governed, in immune cells can be quantified by the surrogate measure of part, by certain definable tumor characteristics associated with intratumoral transcript levels of immune cell–specific genes that intrinsic tumor immunogenicity. are coordinately expressed (8–13). Through hierarchical cluster- In this study, we address the question of how to optimally ing analysis, we and others have demonstrated that these genes stratify breast tumors into subsets that differ in their potential for self-organize into multiple gene clusters that embody signaling protective immune responsiveness. Although a number of immu- networks fundamental to distinct and identifiable immune cell nohistochemical and microarray-based studies have analyzed the subpopulations (12–18). These immune gene signatures or protective effects of relative levels of immune infiltration in breast "metagenes," consistent with the effector cell types they reflect, cancer, none have addressed the question of how to distinguish have been shown by multiple groups to be associated with patient tumors in which elevated immune involvement does or does not outcomes such as disease-free and overall survival (2, 8, 12, 13, 16, confer protective benefit. We hypothesized that the statistical 19–21), response to neoadjuvant chemotherapy (22, 23), and association between the immune metagenes and DMFS of adjuvant molecular therapy (anti-Her2/neu; ref. 24), paralleling patients could be used as a means to extrapolate the underlying historical immunohistochemical observations. breast tumor phenotypes that differ in their ability to potentiate We characterized the underlying biology and prognostic rami- long-term, immune-mediated tumor rejection. Using an immune fications of several distinct immune metagenes in breast cancer metagene model that combines the prognostic attributes of the (12). The term "metagene" is defined here as a cluster of coordi- B/P, T/NK, and M/D metagenes, we define and validate pro- nately expressed genes that together comprise a single cognate liferative and intrinsic subtype attributes of breast cancer that expression vector. By averaging the expression levels of these indicate the existence of immune benefit-enabled (IBE) and genes, a composite expression score can be computed for each immune benefit-disabled (IBD) tumor subtypes, and shed light tumor (25). We showed that the immune metagene scores quan- on the underlying molecular pathways that may contribute to tify the relative abundance of distinct effector cell populations, their differing immunogenic dispositions. namely cytotoxic T and/or NK cells (the T/NK metagene), anti- body-producing plasma B cells (the B/P metagene), and antigen- presenting myeloid/dendritic cells (the M/D metagene). The Materials and Methods expression scores of all three metagenes were significantly asso- Microarray datasets and data processing ciated with prolonged distant metastasis-free survival (DMFS) of All microarray data were obtained from MIAME-compliant patients with breast cancer and displayed additive prognostic (26) data repositories and were associated with IRB-approved information when considered
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