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.
Highlights
T cell co-inhibitory molecules belonging to the B7 family in the tumor microenvironment, such as PD-L1 provide critical inhibitory signals and have been recognized as a major immune inhibitory mechanism in diverse solid tumors.[1,2,3,4] Antibodies that inhibit the PD-1/PD-L1 pathway produce durable clinical responses in various solid malignancies, including breast carcinomas, yet it appears to benefit only a subset of breast tumors.[5,6,7,8,9,10,11]B7-H4 (VTCN1) is a T-cell co-inhibitory molecule and a member of the B7 family
B7-H4 tumor protein expression in the tumor cell component was high in 257/561 (45.8%) of the Yale cohort patients and 198/ 444 (44.6%) of the University of Michigan (UM) cohort patients (Table 1; Supplementary Fig. 1a, b)
In this study, we have observed that the immune checkpoint B7H4 is expressed in the epithelial tumor component of ~50% of breast tumors, and in the stromal element in ~25–30% of cases
Summary
T cell co-inhibitory molecules belonging to the B7 family in the tumor microenvironment, such as PD-L1 provide critical inhibitory signals and have been recognized as a major immune inhibitory mechanism in diverse solid tumors.[1,2,3,4] Antibodies that inhibit the PD-1/PD-L1 pathway produce durable clinical responses in various solid malignancies, including breast carcinomas, yet it appears to benefit only a subset of breast tumors.[5,6,7,8,9,10,11]. B7-H4 (VTCN1) is a T-cell co-inhibitory molecule and a member of the B7 family. It has limited expression in normal peripheral tissues, such as lung epithelium, whereas it is expressed at higher levels in several human cancers, including breast carcinomas[12,13] (Supplementary Table 1). B7-H4 can function as a co-inhibitory factor inhibiting CD4+ and CD8+ T-cell proliferation, cytokine production, and generation of alloreactive cytotoxic T-lymphocytes (CTLs) by arresting the cell cycle.[14,15] In preclinical models, IL-6 and IL-10 can stimulate B7-H4 expression by monocytes, macrophages, and myeloid dendritic cells.[16,17,18] Efforts are ongoing to develop new therapies that target B7-H4.19
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