CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma

Abstract

The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4+CD69+CXCR4+ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis

“…Also, immunohistochemical analysis of CXCR4 expression in 36 patients with NSCLC found that patients with high CXCR4 tumors were more prone to clinical metastasis than patients with low expression tumors (22). Thus, previous reports suggest that CXCL12 and CXCR4 expression might influence the progression of lung adenocarcinoma (8) and NSCLC (22), respectively. While these studies were limited to relatively small populations, we provide statistically significant evidence that strengthens and clarifies the importance of the observations in these studies.…”

“…However, CXCL12 protein levels were present in both tumor and normal lung tissues by ELISA analysis. Other authors also showed that CXCL12 expression was detectable in 42 of 46 NSCLC samples using immunohistochemistry (8). Downregulation of CXCL12 expression in tumor cells was present in other tumor cell lines including breast, cervix, colon, duodenal, gastric, liver, lung, and pancreatic tumor as well as leukemia and melanoma lines (9).…”

“…Notably, immunohistochemical analysis of CXCL12 expression in 46 patients with NSCLC found that disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor (8). Also, immunohistochemical analysis of CXCR4 expression in 36 patients with NSCLC found that patients with high CXCR4 tumors were more prone to clinical metastasis than patients with low expression tumors (22).…”

CD69+CD4+CD25− T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-β1

“…ϩ CD69 ϩ CXCR4 ϩ T cells expressed high CD25 and Foxp3; however, there was no functional study of these T cells as suppressor of T cell proliferation, and the biological significance of CD69 for the function of these T cells was not described (44).…”

Immunobiology of Monocytes/Macrophages in Hepatocellular Carcinoma

“…However, exposure to hepatoma cell culture supernatants did not elicit the IDO expression in monocytes/Mφs, which suggests that additional factors within the tumor milieu are required for inducing IDO expression in tumor Mφs. CD69 is an immunoregulatory molecule expressed by early activated leukocytes at sites of chronic inflammation and CD69 + T cells have been found to promote human tumor progression [80,81]. Upon encountering autologous CD69 + T cells, tumor Mφs acquired capabilities to produce greatly higher amount of IDO protein.…”