Abstract 5268: Impede cancer brain metastasis by enhancing innate immunity with CCL2 targeting

Abstract Among the more than 300, 000 newly diagnosed breast cancer patients every year, 5∼20% of them will develop symptomatic brain metastasis (BrM) with a lower than 20% of 1-year survival rate. Our group previously reported that brain tumor microenvironment (TME)-mediated PTEN downregulation in BrM tumor cells leads to increased secretion of the CCL2 chemokine, which enhances the infiltration of CCR2+ bone marrow derived myeloid cells to promote brain metastasis outgrowth. Here, we further assessed whether targeting CCL2 can effectively inhibit BrM progression. Indeed, targeting CCL2 through either knocking-down CCL2 or with Ccl2-blocking antibody exhibited significant inhibition of BrM growth. Mass cytometry analysis of the brain TME demonstrated dramatically decreased immune suppressive myeloid populations in the CCL2-targeted group, which is consistent with our previous findings. Remarkably, natural killer (NK) and CD8+ T cells were dramatically increased in the TME of CCL2-knockdown BrMs. To test the contribution of the increased NK cells and/or CD8+ T cells on BrM inhibition by CCL2-targeting, we specifically depleted NK cells or CD8+ T cells with anti-NK1.1 or anti-CD8 antibody. Our data showed that depleting NK cells, but not CD8+ T cells, blocked BrM inhibition effect of CCL2-targeting, indicating that the increased infiltration of NK cells significantly contributed to the BrM inhibition under CCL2 knockdown. These findings led us to postulate that CCL2 inhibits NK cell infiltration into BrM TME to facilitate BrM growth. Our in vitro NK cell migration assay with high- versus low-CCL2 tumor cells showed that high CCL2 level inhibited NK cell migration. In summary, our data indicate the potential of CCL2 targeting for controlling breast cancer BrM progression and highlight the pivotal role of NK cell-mediated innate immunity in combating BrM. Citation Format: Yimin Duan, Lin Zhang, Yutao Qi, Xiangliang Yuan, Dihua Yu. Impede cancer brain metastasis by enhancing innate immunity with CCL2 targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5268.