Open AccessB7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
Author(s) -
Takeaki Miyamoto,
Ryusuke Murakami,
Junzo Hamanishi,
Kenji Tanigaki,
Yuko Hosoe,
Nathan Mise,
Shiro Takamatsu,
Yuka Mise,
Masao Ukita,
Mana Taki,
Koji Yamanoi,
Naoki Horikawa,
Kaoru Abiko,
Ken Yamaguchi,
Tsukasa Baba,
Noriomi Matsumura,
Masaki Mandai
Publication year - 2021
Publication title -
cancer immunology research
Language(s) - English
Resource type - Journals
eISSN - 2326-6074
pISSN - 2326-6066
DOI - 10.1158/2326-6066.cir-21-0407
Subject(s) - ccr2 , tumor microenvironment , cancer research , ccl2 , cd163 , cd8 , tumor progression , stromal cell , macrophage , ovarian cancer , immunotherapy , biology , tumor associated macrophage , cancer , immune system , immunology , medicine , chemokine , chemokine receptor , in vitro , biochemistry
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.