Interferon-inducible CXC-chemokines are crucial immune modulators and survival predictors in colorectal cancer
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Larissa Kistner1,*, Dietrich Doll1,2,*, Anne Holtorf1, Ulrich Nitsche1 and Klaus-Peter Janssen1
1Department of Surgery, Klinikum rechts der Isar, TUM, Munich, Germany
2Current/Present Address: St. Marienhospital Vechta, Vechta, Germany
*These authors have contributed equally to this work
Klaus-Peter Janssen, email: [email protected]
Keywords: colorectal cancer, tumor immunology, mouse model, chemokines
Received: July 12, 2017 Accepted: August 26, 2017 Published: September 28, 2017
Tumor-infiltrating T-cells are strongly associated with prognosis in colorectal cancer, but the mechanisms governing intratumoral lymphocyte recruitment are unclear. We investigated the clinical relevance and functional contribution of interferon-regulated CXC-chemokines CXCL9, CXCL10, and CXCL11, described as T-cells attractants. Their expression was significantly elevated in tumors as compared to normal colon in 163 patients with colon cancer, represented an independent positive predictor of post-operative survival, and was highly significantly correlated with the presence of tumor-infiltrating cytotoxic CD8+ T-cells and CD4+ TH1-effector cells. The regulation of chemokine expression was investigated in established cell lines and in tissue explants from resected tumor specimen (n=22). All colorectal cancer cell lines tested, as well as stroma or endothelial cells, produced CXC-chemokines in response to cytokine stimulation. Moreover, resected tumor explants could be stimulated to produce CXC-chemokines, even in cases with initially low CXC-levels. Lastly, a causative role of chemokine expression was evaluated with an orthotopic mouse model, based on isogenic rectal CT26 cancer cells, engineered to express CXCL10. The orthotopic model demonstrated a protective and anti-metastatic role of intratumoral CXCL10 expression, mediated mainly by adaptive immunity.
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