B7-H3 suppresses anti-tumor immunity via the CCL2-CCR2-M2 macrophage axis and contributes to ovarian cancer progression
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons sanguins ou tumoraux issus de patientes atteintes d'un cancer séreux de l'ovaire de haut grade, cette étude met en évidence un mécanisme par lequel la protéine B7-H3 de la membrane des cellules cancéreuses, via les macrophages M2, le ligand CCL2 et le récepteur CCR2, supprime l'immunité antitumorale et favorise la progression tumorale
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, non-immunoreactive 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 HGSOC patients, 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 immunological TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.