CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity.
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.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.|Department of Head and Neck Surgery, Sichuan Cancer Hospital, Sichuan University, Chengdu, P. R. China.
Guiquan
G
Zhu
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
H Hannah
HH
Yan
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.|Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, P. R. China.
Yanli
Y
Pang
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.|Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P. R. China.
Jiang
J
Jian
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Bhagelu R
BR
Achyut
Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P. R. China.
Xinhua
X
Liang
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, USA.
Jonathan M
JM
Weiss
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, USA.
Robert H
RH
Wiltrout
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
M Christine
MC
Hollander
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Li
L
Yang
D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000276:immunology* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism*
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3
CXCR3; drug treatment; host immunity; migration; tumor metastasis