B7-H1 and B7-H4 expression in colorectal carcinoma: Correlation with tumor FOXP3+ regulatory T-cell infiltration
Introduction
Colorectal carcinoma (CRC) is one of the most frequent malignancies worldwide, and it is the second leading cause of cancer-related deaths in the world (Herszényi and Tulassay, 2010). Clinically, because of advances in surgical technology, radiotherapy and the use of powerful chemotherapeutics, the CRC prognosis has markedly improved. Nevertheless, 40–50% of CRC patients are confronted with recurrence and metastasis. Clearly it is necessary to explore the tumorigenesis in order to develop novel therapies for the treatment of CRC, and one possibility is an immunotherapeutic approach to correct the abnormal immunity (Koudougou et al., 2013).
The B7 protein family provides both stimulatory and inhibitory regulation of T cell responses, depending on which B7 ligand and receptor is engaged on the target cell (Carreno and Collins, 2002, Khoury and Sayegh, 2004). B7-H1 is an identified member of the B7 family as a co-stimulatory molecule. B7-H1 is expressed on immunocompetent cells such as T cells, B cells, dendritic cells (DCs), and macrophages (Yamazaki et al., 2005). With engagement of programmed cell death 1(PD-1) receptor, B7-H1 molecule presenting on DC influences the hindrance of T cell proliferation depending on T cell receptor (TCR) and the decrease in cytokine production (Mirza et al., 2010). Furthermore, the interaction of B7-H1–PD-1 plays a critical role in suppressing T cell-based immunity and has emerged as an essential mediator of tumor-associated immune suppression (Ichikawa and Chen, 2005). B7-H4 was identified in 2003 as a co-stimulatory molecule. It is also a ligand within the B7 family and it is vital in the process of hindering the proliferation of T cells and blocking the production of cytokines by Th1 and Th2 sub-populations (Sica et al., 2003, Zheng et al., 2012). B7-H4 mRNA expression was found to be widely distributed in the peripheral tissues. However, B7-H4 protein expression on the cells is primarily restricted to activated T cells, B cells, monocytes, and DCs (Sica et al., 2003, Choi et al., 2003). B7-H4 is not detected in the majority of normal tissues and cells, but is found in a variety of tumor tissues, mainly expressed in tumor cells and tumor infiltrating macrophages (Salceda et al., 2005, Sun et al., 2006, Tringler et al., 2006, Zang et al., 2007). Collectively, these findings suggest that B7-H1 and B7-H4 may function as a negative mediator of immune responses through different pathways in anti-tumor immunity (Ichikawa and Chen, 2005, Janakiram et al., 2012).
Regulatory T cells (Tregs) are a unique CD4+ helper T cell subset and are characterized by the CD4+CD25+ phenotype. Forkhead box protein 3 (FOXP3) belongs to the forkhead/winged-helix family of transcriptional regulators and appears to function as a master regulator in the development and control of Tregs. FOXP3 has been regarded as the most specific and reliable surface marker of Tregs (Fontenot et al., 2003, Hori et al., 2003, Khattri et al., 2003). Tregs have been found in a number of human tumors, and their presence has been associated with impeding immune escape against autologous tumor cells (Nomura and Sakaguchi, 2005). Furthermore, B7-H1 expression is associated with expansion of Tregs in the tumor microenvironment (Ni et al., 2012). Kristensen et al. (2013) showed that treatment with B7-H4-Ig fusion protein in vivo changes lymphocyte homeostasis and increases the functional activity of Tregs (Kristensen et al., 2013). Thus, our hypothesis is that there is a strong link between expression of inhibitory B7 molecules by the cancer cells and Tregs infiltrated into the tumor environment. In this report, we performed immunohistochemistry to characterize B7-H1 and B7-H4 expressions in human CRC. Tregs were also detected in the tumor tissues and the relationship between inhibitory B7 molecules and Tregs population was analyzed.
Section snippets
Patients and tissue specimens
Fifty six fresh CRC samples and fifty-six normal colorectal mucosa samples obtained from >5 cm from the tumor margin were used in this study. Fresh specimens were cut to blocks of 1–2 cm and embedded in optimum cutting temperature (OCT) compound after separation, quickly frozen in isopentane surrounded by liquid nitrogen until sectioning. All samples were collected from the patients who underwent surgical resection between 2007 and 2009 at the Affiliated Hospital of Beihua University. This study
B7-H1 and B7-H4 expressions in colorectal tissues
B7-H1 and B7-H4 were expressed in cytoplasm and membrane of the tumor cells, especially in the intestinal gland epithelial cells (Fig. 1A and C), but tumoral infiltrating lymphocytes lacked staining. B7-H1 and B7-H4 immunostaining was negative in most adjacent normal mucosa tissue (Fig. 1B and D) and was weakly positive in the epithelial cytoplasm of intestinal gland. In 56 normal colorectal tissues adjacent to the tumor samples, there were five (8.93%) cases that were B7-H1 weakly positive and
Discussion
Tumor cells can be recognized and attacked by antigen-specific T cells. However, the B7 family plays a central role in the positive and negative regulation of antigen-specific T cell-mediated immune responses. The up-regulation of inhibitory B7 molecules may result in immunosuppression through the suppression of function of T cells and thus contribute to tumor immune evasion (Zou and Chen, 2008).
B7-H1 and B7-H4 are newly discovered B7 family members providing negative signals to limit,
Acknowledgements
This study was supported by Grant No. 2014177 from the Department of Education of Jilin Province and National Natural Science Foundation of China (Grant No. 81170632).
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2019, Journal of Controlled ReleaseCitation Excerpt :Furthermore, evidence demonstrates the pivotal role of PD-L1 in the development and maintenance of Tregs [101]. Recent studies have indicated a correlation between PD-L1 level and increased Treg trafficking in several types of cancer such as colorectal and breast cancer [102–104]. Therefore, inhibition of Treg and MDSC infiltration in the tumor by inhibiting the chemokine receptors expressed abundantly in these cells may prevent immune suppression and enhance anticancer T cell killing.