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NPJ Breast Cancer. 2018 Dec 10;4:40. doi: 10.1038/s41523-018-0095-1. eCollection 2018.

Association of B7-H4, PD-L1, and tumor infiltrating lymphocytes with outcomes in breast cancer.

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1Section of Medical Oncology, Yale School of Medicine, New Haven, CT USA.
2Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX USA.
3Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI USA.
4Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI USA.
5Department of Pathology, Yale School of Medicine, New Haven, CT USA.
6Anatomic Pathology, Clinica Alemana-Facultad de Medicina Universidad de Desarrollo, Vitacura, Santiago Chile.


B7-H4 (VTCN1) is a member of the CD28/B7 family of immune co-inhibitory molecules. The relationship of tumor and stromal B7-H4 protein expression with PD-L1, tumor infiltrating lymphocytes (TILs) and its association with clinico-pathological variables are not well defined. Herein, we explore the expression level of B7-H4 protein in breast cancer and evaluate its association with TILs, levels of PD-L1 expression, and clinico-pathological characteristics in two independent populations. In this study, we used multiplexed automated quantitative immunofluorescence (QIF) to measure the levels of B7-H4 and PD-L1 protein and determined TILs through pathologist assessment of H&E-stained preparations in over a thousand breast cancer cases from two institutions represented in tissue microarray format. Associations between the marker levels, major clinico-pathological variables, and survival were analyzed. We detected B7-H4 protein was highly expressed in both breast cancer and stromal cells. Its expression was independent of breast cancer intrinsic subtypes. PD-L1 expression was higher in triple negative breast cancers. Neither B7-H4 nor PD-L1 were associated with survival in breast cancer. Our study shows there is a mutually exclusive pattern of B7-H4 with both tumor PD-L1 expression and TILs in all breast cancers, independent of breast cancer intrinsic subtype. This exclusive pattern suggests that some breast tumors may preferentially use one B7-related immune evasion mechanism/pathway. This could explain the clinical benefit that is seen only in a fraction of patients with immune checkpoint inhibitors directed exclusively towards PD-L1 in breast cancer.

Conflict of interest statement

D.L.R. is a consultant/advisor to Astra Zeneca, Agendia, Agilent, Bethyl Labs, Biocept, BMS, Cell Signaling Technology, Cepheid, Merck, OptraScan, Perkin Elmer, and Ultivue. Holds equity in PixelGear. Astra Zeneca, Cepheid, Navigate/Novartis, Gilead Sciences, Ultivue, and Perkin Elmer funds research in Rimm’s lab. The remaining authors declare no competing interests.

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