Tumour-infiltrating FOXP3+ lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer

Autor: Sara E. Kost, Peter H. Watson, Spencer D. Martin, Katy Milne, Brad H. Nelson, R. J. deLeeuw, Nathan R. West
Rok vydání: 2012
Předmět:
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
DOI: 10.1038/bjc.2012.524
Popis: Tumour-infiltrating lymphocytes (TIL) are associated with patient survival in a wide variety of tumour types (Pages et al, 2010). In the case of breast cancer, several studies have demonstrated that gene expression patterns indicative of high TIL content are associated with improved clinical outcome, particularly among tumours with aggressive clinical features such as high histological grade or oestrogen receptor-α (ERα)-negative status (Teschendorff et al, 2007; Desmedt et al, 2008; Schmidt et al, 2008; Calabro et al, 2009; Rody et al, 2009). Several groups have extended these observations by using immunohistochemistry (IHC) to demonstrate that high levels of CD8+ TIL (cytotoxic T cells (CTLs)) are associated with good outcome in breast cancer (Mahmoud et al, 2011a; Liu et al, 2012). The opposite, however, appears to be true of FOXP3+ TIL. FOXP3 is a forkhead family transcription factor that is essential for the development and function of regulatory T cells. Tregs are operationally identified by expression of CD4, CD25, and FOXP3, with FOXP3 being the most commonly used single marker (Campbell and Ziegler, 2007; Sakaguchi et al, 2008). Under normal conditions, Tregs are essential suppressors of inappropriate immune responses and thus maintain immunological tolerance to host tissues (Sakaguchi et al, 2008). Their suppression of anti-tumour immunity, however, is considered to be deleterious. Indeed, the presence of FOXP3+ TIL has been associated with poor clinical outcome in a wide variety of cancer types, fuelling speculation that depletion of Tregs in cancer patients could have beneficial therapeutic effects (deLeeuw et al, 2012). Nevertheless, a growing number of studies demonstrate that FOXP3+ TIL can also be associated with a favourable prognosis (reviewed in deLeeuw et al, 2012). Although this discordance is not currently understood, it is possible that the prognostic impact of FOXP3+ TIL depends on the molecular characteristics of a given tumour type. To date, several studies of breast cancer have shown a consistent association between FOXP3+ TIL and poor clinical outcome (Bates et al, 2006; Aruga et al, 2009; Gobert et al, 2009; Liu et al, 2011; Yan et al, 2011; Mahmoud et al, 2011b). Although none of these studies focused on specific histological or molecular subtypes of breast cancer, FOXP3+ TIL showed a consistent association with ER-negative (ER–) tumours, which are biologically and clinically distinct from ER+ lesions (Foulkes et al, 2010). Because TIL have been shown to associate with good outcome primarily in ER– tumours (Teschendorff et al, 2007; Desmedt et al, 2008; Calabro et al, 2009; Rody et al, 2009), and because FOXP3+ TIL are inherently associated with ER negativity (Bates et al, 2006; Bohling and Allison, 2008; Ghebeh et al, 2008; Aruga et al, 2009; Liu et al, 2011; Mahmoud et al, 2011b; Yan et al, 2011), we chose to investigate the clinical impact of FOXP3+ TIL in ER– breast cancer. Importantly, we found that high numbers of FOXP3+ TIL are associated with dense infiltrates of CD8+ TIL and favourable prognosis.
Databáze: OpenAIRE
Externí odkaz: