Immunogenic subtypes of breast cancer delineated by gene classifiers of immune responsiveness

Lance D. Miller, Jeff A. Chou, Michael A. Black, Cristin Print, Julia Chifman, Angela Alistar, Thomas Putti, Xiaobo Zhou, Davide Bedognetti, Wouter R. Hendrickx, Ashok Pullikuth, Jonathan Rennhack, Eran R. Andrechek, Sandra Demaria, Ena Wang, Francesco M. Marincola

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35 Citations (Scopus)


The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis- free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell-specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2- enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFa/IFNg signaling pathways in IBE tumors and the activation of the transforming growth factor-b pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation.

Original languageEnglish
Pages (from-to)600-610
Number of pages11
JournalCancer immunology research
Issue number7
Publication statusPublished - 1 Jul 2016


ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Miller, L. D., Chou, J. A., Black, M. A., Print, C., Chifman, J., Alistar, A., Putti, T., Zhou, X., Bedognetti, D., Hendrickx, W. R., Pullikuth, A., Rennhack, J., Andrechek, E. R., Demaria, S., Wang, E., & Marincola, F. M. (2016). Immunogenic subtypes of breast cancer delineated by gene classifiers of immune responsiveness. Cancer immunology research, 4(7), 600-610.