Abstract
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.
Highlights
Cancer of colon and rectum is amongst the most common malignancies [1]
We previously identified chemokines CXCL9, CXCL10, and CXCL11, as well as GZMB (Granzyme B), as part of a prognostic gene signature in colon cancer
We validated the transcriptome findings on an independent patient collective by quantitative realtime-PCR, confirming their up-regulated expression in a patient collective with colorectal carcinoma, representing all stages of the disease (n=163 cases; clinical data summarized in Supplementary Table 1), compared to normal colon mucosa from 28 patients (Figure 1A)
Summary
Cancer of colon and rectum is amongst the most common malignancies [1]. the current tumor staging system is not well suited for individualized risk assessment [2]. CXC-chemokine signaling regulates angiogenesis and recruitment of immune cells [5], it connects cancer cells and the surrounding stroma [6]. CXCL9 (MIG), CXCL10 (IP10) and CXCL11 (ITAC) are IFNγ inducible chemokines of the CXC-family [7, 8]. These chemokines have angiostatic function and are pivotal for the recruitment and activation of leukocytes, mediated by binding to receptor CXCR3, preferentially expressed on activated T cells [9]. The mechanism underlying T-cell infiltration into solid tumors is not well understood, and the contribution of interfon-regulated CXC-chemokines is under debate [20]. A causal in vivo role of CXCR3-ligands was assessed with the help of an orthotopic colon cancer model
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