Abstract
Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.
Highlights
Metastasis of epithelial tumor cells critically depends on acquisition of a disseminating phenotype that allows tumor cells to migrate, invade, and colonize in distant organs
To investigate the role of CXCR3 in breast cancer metastasis, we used the 4T1 mammary tumor model, which shares many characteristics with human breast cancer, its ability to spontaneously metastasize to the lungs
We report that genetic targeting of CXCR3 in both tumor cells and host-derived cells showed tumor-inhibitory effect
Summary
Metastasis of epithelial tumor cells critically depends on acquisition of a disseminating phenotype that allows tumor cells to migrate, invade, and colonize in distant organs. The metastatic process requires the participation of a host compartment [1,2,3,4]. One major challenge is the selection of therapy that can target cancer cells efficiently, and avoid an adverse effect on the host compartment www.impactjournals.com/oncotarget and preferably improve host anti-tumor immunity. Our understanding of the molecular mechanisms underlying both tumor and host compartments during the metastatic process is critical for cancer therapy to be more effective and less toxic
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