| RRC ID |
70105
|
| 著者 |
Miyamoto T, Murakami R, Hamanishi J, Tanigaki K, Hosoe Y, Mise N, Takamatsu S, Mise Y, Ukita M, Taki M, Yamanoi K, Horikawa N, Abiko K, Yamaguchi K, Baba T, Matsumura N, Mandai M.
|
| タイトル |
B7-H3 Suppresses Antitumor Immunity via the CCL2-CCR2-M2 Macrophage Axis and Contributes to Ovarian Cancer Progression.
|
| ジャーナル |
Cancer Immunol Res
|
| Abstract |
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 IFNγ 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 IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2-CCR2 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 IFNγ+CD8+ 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.
|
| 巻・号 |
10(1)
|
| ページ |
56-69
|
| 公開日 |
2022-1-1
|
| DOI |
10.1158/2326-6066.CIR-21-0407
|
| PII |
2326-6066.CIR-21-0407
|
| PMID |
34799346
|
| MeSH |
Animals
B7 Antigens / genetics
B7 Antigens / immunology*
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology
Cell Line, Tumor
Chemokine CCL2 / genetics
Female
Humans
Immune Tolerance
Lymphocytes, Tumor-Infiltrating / immunology
Macrophages / immunology
Mice
Mice, Inbred C57BL
Mice, Nude
Ovarian Neoplasms / immunology*
Ovarian Neoplasms / therapy*
Receptors, CCR2 / genetics
Transcription Factors / metabolism
Tumor Microenvironment / immunology
Xenograft Model Antitumor Assays
|
| IF |
8.728
|
| リソース情報 |
| ヒト・動物細胞 |
OV2944-HM-1(RCB1483) |
