Tumor angiogenesis, a hallmark of cancer, is a critical step in the tumorigenesis of solid cancers . The process of tumor angiogenesis is orchestrated by a range of secreted factors, signaling pathways as well as nonendothelial cells . Abnormal tumor vascular networks sometimes contribute to a decline in the efficacy of various therapies, such as chemotherapy, radiotherapy, and immunotherapy [3,4]. Anti-angiogenesis via targeting VEGF-mediated signaling has become one of the most promising therapies, which aimed at inhibiting VEGF activity to regress tumors by starvation . In 2003, a clinical trial demonstrated that chemotherapy combined with bevacizumab (humanized neutralizing antibodies targeting VEGF) improved the clinical survival of metastatic colorectal cancer (CRC) patients . After bevacizumab receiving the FDA (the Food and Drug Administration) approval , the FDA has approved various angiogenic inhibitors as cancer therapies. Unfortunately, emerging clinical evidence indicated that the benefit of these anti-angiogenic treatments have so far shown only modest clinical efficacy and remained to be suboptimal in patients who lack responses or acquire resistance.
Immune checkpoint inhibitors (ICIs) have shown a long-lasting clinical activity against a large number of malignancies , which re-start the anti-tumor immune responses of the host via inhibiting the negative regulatory immune signals of T cells . In the last decade, cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death receptor 1 (PD-1) and its ligand, PD-L1 inhibitors have made remarkable progress in the clinical application of cancer immunotherapies . Ipilimumab, an anti-CTLA-4 antibody, was granted FDA approval in 2011 and improved the overall survival of patients with advanced melanoma . Furthermore, pembrolizumab and nivolumab, anti-PD-1 antibodies, were approved for the advanced melanoma treatment in 2014 [12,13]. However, the response rates of single antibody blocking PD-1 or CTLA-4 pathway remain low in a majority of patients [14,15]. To overcome this problem, a rationale for the combination of therapies with ICIs and conventional therapies such as chemotherapy, radiotherapy, and anti-angiogenesis therapy, started to be considered.
Previous evidence showed that angiogenesis played a key role in regulating tumor immune response and lead to resistance to ICIs . VEGF family, which induces physiological and pathological angiogenesis , has been reported to suppress tumor immune response by enhancing T cell exhaustion by upregulating PD-L1, CTLA-4, TIM3 and LAG3 expression on T-cells . Besides, VEGF promoted the expansion of T-regulatory cells (T-regs) and Myeloid-derived suppressor cell (MDSCs) and the infiltration of tumor-associated macrophages (TAMs) in tumors . Conversely, the immune microenvironment is also able to affect the tumor angiogenesis. Huang et al. reported that IL-35 recruits monocytes via CCL5 and induces macrophages to promote angiogenesis through inducing CXCL1 and CXCL8 expression in pancreatic ductal adenocarcinoma cells . CD11b+Gr-1+ MDSCs contributed to lung metastasis of breast cancer by inducing angiogenesis in a platelet-derived growth factor-BB dependent manner . Therefore, the mutual interactions between tumor angiogenesis and immunosuppressive microenvironment may be a key cause of the failure of single anti-angiogenesis therapy or ICIs.
B7-H3 (B7 homolog 3 protein), also known as CD276, belongs to the B7-CD28 immune checkpoint family and takes part in cancer development and cancer immunity . We have previously shown that B7-H3 is significantly upregulated in CRC tissue samples compared with normal adjacent tissues, and is positively associated with TNM stages . Current research results also demonstrated that the upregulation of B7-H3 is closely related to lymph node metastasis in patients with CRC. Other groups have also shown that B7-H3 is overexpressed in multiple malignant tumors, and is associated with poor prognosis [24,25]. These results suggest that B7-H3 exerts crucial effects on tumor progression.
B7-H3 has been reported to exert a costimulating effect on the proliferation and IFN-γ production of T cells [26,27]. By contrast, other studies have shown that B7- H3 plays an inhibitory role in T cell proliferation . Although the immunologic function of B7-H3 remains controversial, B7-H3 has been a potential target for cancer immunotherapy. Du and colleagues generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3. CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer, and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models . In addition, B7- H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells . In ID8 ovarian cancer mouse models, B7-H3 expressed on tumor cells, but not host cells, had a dominant role in suppressing the function of CD8+ T cells . Moreover, B7-H3 blockade, but not PD-1 blockade, prolonged the survival of ID8 tumor-bearing mice . Therefore, B7- H3 may be a promising immune therapeutic target for tumors.
Aside from its immunologic function, B7-H3 has been reported to participate in multiple non-immunological functions in cancers, such as proliferation, metastasis, drug resistance and metabolism . Previous reports from our group have shown that B7-H3 plays an important role in metabolism and chemoresistance in CRC [23,33]. Body of evidence has revealed that B7- H3 participates in the progression and metastasis of CRC, indicating that B7-H3 has become a new potential prognostic marker and therapeutic target for CRC . More importantly, B7-H3 has been found to take part in the anti-angiogenesis in cancers. A prior study has shown that the expression of B7-H3 dramatically differs between physiological and pathological angiogenic vessels and is remarkably upregulated in the blood vessels of various human cancers . In our current research, our data indicated that the expression level of B7-H3 is a positive association with CD31, a sensitive and specific endothelial marker for MVD in CRC tissue samples. Seaman et al. demonstrated that pyrrolobenzodiazepineconjugated anti-B7-H3-drug can target both angiogenic vessels and non-angiogenic vessels, showing promising antitumor activity while little toxicity . Furthermore, a series of in vitro and in vivo experiments showed that B7-H3 on CRC cells upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Therefore, B7-H3 may promote angiogenesis by upregulating the expression of VEGFA in CRC, showing its great prospect of a possible biomarker in personalized anti-angiogenic therapy.
Nowadays, it is believed that combining an immune checkpoint inhibitor (ICI) with anti-angiogenesis would become a promising strategy, which can overcome the treatment resistance and finally improve patients’ prognosis . We are aware that it seems to be a twoway street between anti-angiogenic therapies and immunotherapies, whose efficacy influence with each other . Excessive levels of VEGF contribute to VEGFinduced immunosuppression in tumors . The clinical success in the combination of VEGF inhibitors and ICI therapy attributed to the VEGF inhibitors, suppressing VEGF-induced immunosuppression and promoting an anti-tumor immune response . Given that B7-H3 not only exerts crucial regulatory effects on the anti-tumor immune but also plays key roles in tumor angiogenesis, combination therapy with B7-H3 blockade and antiangiogenesis may be a particularly valuable option for the treatment of cancers. In our current research, we showed that the combination therapy of B7-H3 inhibitor 3E8 with bevacizumab inhibited the tumor growth, showing a more inhibitory effect on the MVD and VEGFA expression in mouse xenograft models (Figure 1). As such, it is expected that combination therapy with B7-H3 blockade and anti-angiogenesis is applied to the clinical treatment of tumors.
This work was supported by the National Natural Science Foundation of China (No.81802843, No.81672372).
Conflict of Interest
The authors declare no conflict of interest.
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