Host B7x Promotes Pulmonary Metastasis of Breast Cancer

Abstract

B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues such as the lung epithelium, but over-expressed in a variety of human cancers with negative clinical associations including metastasis. However, the function of B7x in the cancer context, whether expressed on cancer cells or on surrounding “host” tissues, has not been elucidated in vivo. We utilized the 4T1 metastatic breast cancer model and B7x knockout (B7x−/−) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo and B7x−/− mice had significantly fewer lung 4T1 tumor nodules than wildtype mice. Furthermore, B7x−/− mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor associated neutrophils (TANs), macrophages, and regulatory T cells into tumor-bearing lungs. Importantly, the TANs strongly bound B7x protein and inhibited proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local anti-tumor immune responses through interactions with the innate as well as the adaptive immune systems. Targeting the B7x pathway thus holds much promise for improving the efficacy of immunotherapy for metastatic cancer.

Higher preoperative serum levels of PD‐L1 and B7‐H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF‐targeted therapy and unfavorable prognosis of renal cell carcinoma

“…In an experimental model of lung metastasis, B7‐H4 expression by host cells was demonstrated to suppress tumor‐specific T‐cell responses and promote the infiltration of immunosuppressive T‐cell subsets into the lungs. As a result, B7‐H4 WT mice had more lung metastases than B7‐H4 knockout mice 28. Expression of B7‐H4 was also reported to show a correlation with tumor infiltration by Treg cells 29.…”

B7-H4 Expression is Associated with Cancer Progression and Predicts Patient Survival in Human Thyroid Cancer

“…It has been shown that the activation of the B7-H4 signaling pathway may lead to tumor cells escaping from immune surveillance (Flies and Chen, 2007;Arigami et al, 2011;Sun et al, 2012). Recent report showed that host B7-H4 may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems (Abadi et al, 2013). Several evidences have demonstrated that the B7-H4 molecule promotes cancer progression via regulating T cell mediated antitumor immunity (Zang et al, 2003;Sica et al, 2003;Sun et al, 2012).…”

“…Recently, B7-H4 has been reported to be highly expressed in human cancer cells, and their protein levels in tumors significantly correlate with patients' clinicopathological features and postoperative prognosis (Miyatake et al, 2007;Awadallah et al, 2008;Arigami et al, 2011;Abadi et al, 2013). However, no reports have investigated the clinical significance of B7-H4 expression in patients with thyroid cancer.…”

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

“…B7x binds activated T cells and inhibits T-cell functions. In addition, myeloid-derived suppressor cells (MDSCs) also express a receptor for B7x (30). Clinical data also support a coinhibitory function for B7x, as aberrant expression of this molecule is observed in many types of human cancers and is often associated with enhanced disease progression and poor clinical outcome (31).…”