B7-H4 plays a significant role in tumor escape from the immune surveillance . While the mechanism is still not clear, sB7-H4 may also play a role in cancer development through negative regulation of T-cell immunity. So far, there is no evidence in the literature comparing sB7-H4 blood serum levels with clinical characteristics and outcomes of patients with early BC. Here, we assessed changes in sB7-H4 blood serum levels in paired pre-NACT and post-NACT as well as adjuvant serum samples and correlated these findings with clinico-pathological parameters and prognosis. Although we observed higher sB7-H4 levels after therapy, there were no significant associations between sB7-H4 and prognosis in the neo-adjuvant setting. In addition, no differences in sB7-H4 levels could be documented for the different BC subtypes.
Expression of B7-H4 in tumor tissue has been linked to a worse prognosis in some types of cancer . However, data in the context of BC are inconsistent. Huang et al. showed that the OS rate of patients with higher B7-H4 expression was significantly worse than in those with lower expression . Similarly, TNBC patients with B7-H4 overexpression had significantly shorter survival and recurrence time than those with low B7-H4 expression . These data suggest that B7-H4 might be a potential negative prognostic indicator.
In contrast, other studies showed that B7-H4 expression was not associated with worse survival in BC , and expression of B7-H4 has even been linked to a favorable 5-year PFS . There is no data available with regard to the prognostic features of sB7-H4 in BC patients. We found that sB7-H4 was not associated with prognosis, however, due to the limited data in some BC subgroups, we could not perform subgroup analyses for survival in the adjuvant setting. Nevertheless, we speculate that sB7-H4 may be a part of tumor-immune tolerance because B7-H4 is a negative regulator of immune response which might be important for BC patients. Treatment with antibodies targeting B7-H4 may result in a reduction of tumor progression and better patient outcomes. Indeed, an in vivo study using humanized animal model showed that a B7-H4/CD3-bispecific antibody might be a therapeutic agent against B7-H4-expressing tumors . Therefore, it is essential to identify biomarkers that can predict the possible response to anti-B7-H4 treatment. The existence of sB7-H4 could be a predictive marker for immunotherapy targeting T lymphocytes as suggested by Ohki et al .
B7-H4 is frequently expressed on tumor cells including BC. Data on the expression among particular intrinsic subtypes of BC— defined by expression of ER, PR or HER2—is inconsistent [20, 21]. In our study, sB7-H4 was independent of intrinsic BC subtypes. Since the source and function of sB7-H4 is not known, it is not clear whether serum sB7-H4 reflects the expression of B7-H4 in tumor tissue. Kamimura et al. demonstrated that sB7-H4 is secreted in inflammatory environments  and it was also reported to act as a decoy molecule that blocks suppressive functions of cell-associated B7-H4 leading to enhanced T-cell-mediated autoimmune responses . Zhang et al. suggested that different origins of sB7-H4 define its distinct structure and function . Nevertheless, there is a growing body of evidence indicating that sB7-H4 negatively regulates T-cells and plays a regulatory role in immune tolerance [26, 27].
On the other hand, chemotherapy may have beneficial effects on anticancer immunity by enhancing mutational load or direct elimination of immunosuppressive cells [28–30]. Thus, understanding the effect of DNA-damaging agents on the immune system is critical to identify optimal strategies that combine checkpoint inhibitors and chemotherapy agents. In our study, the detection of serum sB7-H4 almost doubled after NACT versus before NACT. Some preclinical studies have suggested that immune checkpoint expression like Programmed Cell Death Ligand 1 (PD-L1) might be stimulated by chemotherapy; others observed a significant decrease in PD-L1 expression after NACT in BC patients [31, 32]. The changes collectively induced by NACT in immune-checkpoint expression could provide a rationale for the use of immune checkpoint inhibitors in the neoadjuvant setting for BC patients.
The primary limitation of this study is its retrospective character, the lack of corresponding B7-H4 tissue availability and its expression in the tumor microenvironment. However, our study performed on a representative group of BC patients suggests a lack of an association between sB7-H4 serum levels and prognosis. Therapeutic properties of anti-B7-H4 therapy in BC patients is still not known. Since B7-H4 remains a candidate for targeted inhibition in cancer immunotherapy, further prospective studies with blockade of B7-H4 in association with sB7-H4 levels should be proposed to investigate the applicability to anti-B7-H4 immune therapy in BC.