期刊
CANCER IMMUNOLOGY RESEARCH
卷 10, 期 1, 页码 56-69出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-21-0407
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [18K16769, 20K18210]
- Grants-in-Aid for Scientific Research [18K16769, 20K18210] Funding Source: KAKEN
This study explored the immunosuppressive effect of B7-H3 in high-grade serous ovarian cancer (HGSOC) and found that it contributes to immune suppression and tumor progression through the CCL2-CCR2-M2 macrophage axis. These findings provide new insights into the immunologic tumor microenvironment and could aid the development of new therapeutic approaches.
New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2-CCR2-M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1-low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFN gamma signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFN gamma(+) CD8(+) T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2-CCR 2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3-high tumors had fewer tumoral IFN gamma(+) CD8 c T cells and poorer prognosis than patients with B7-H3-low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2-CCR2-M2 macrophage axis-mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.
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