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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.

Author information

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

Abstract

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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