Article

Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: Cohort study and literature review

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
The Journal of Pathology (Impact Factor: 7.43). 12/2010; 222(4):350-66. DOI: 10.1002/path.2774
Source: PubMed

ABSTRACT

The abundance of tumour-infiltrating T-cells has been associated with microsatellite instability (MSI) and a favourable prognosis in colorectal cancer. However, numerous molecular alterations have been associated with clinical outcome, and potentially confounding the biological and prognostic significance of tumour-infiltrating T-cells. We utilized a database of clinically and molecularly-annotated colon and rectal carcinoma cases (N = 768; stage I-IV) in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study) and quantified the densities of CD3(+), CD8(+), CD45RO(+) (PTPRC), and FOXP3(+) cells within neoplastic epithelial areas using an Ariol image analysis system and tissue microarray. We used Cox proportional hazard models to compute the mortality hazard ratio, adjusting for clinical and molecular features including KRAS, BRAF, and PIK3CA mutations, MSI, CIMP, and LINE-1 hypomethylation. The densities of CD8(+), CD45RO(+), and FOXP3(+) cells were significantly associated with patient survival in univariate analyses (P(trend) < 0.007). In the multivariate model, tumour-infiltrating CD45RO(+)-cell density, but not CD3(+), CD8(+) or FOXP3(+)-cell density, was significantly associated with survival (p = 0.0032). In multivariate linear regression analysis, MSI-high (p < 0.0001) and high-level tumour LINE-1 methylation (p = 0.0013) were independently associated with higher CD45RO(+)-cell density. The survival benefit associated with CD45RO(+) cells was independent of MSI and LINE-1 status. In conclusion, tumour-infiltrating CD45RO(+)-cell density is a prognostic biomarker associated with longer survival of colorectal cancer patients, independent of clinical, pathological, and molecular features. In addition, MSI-high and tumour LINE-1 methylation level are independent predictors of CD45RO(+)-cell density. Our data offer a possible mechanism by which MSI confers an improved clinical outcome and support efforts to augment the host immune response in the tumour microenvironment as a strategy of targeted immunotherapy.

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Available from: Katsuhiko Nosho
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    • "The presence of tumour-infiltrating lymphocytes (TILs) is associated with improved clinical outcome in many cancers (Cho et al, 2003; Zhang et al, 2003; Hiraoka et al, 2006; Loi et al, 2013). In colorectal cancer, the density of tumour-infiltrating T cells is a strong prognostic indicator, even after adjustment for clinical and molecular risk factors (Pages et al, 2005; Galon et al, 2006; Nosho et al, 2010). The recently developed Immunoscore, which involves assessment of T-cell density in the central tumour and invasive margin based on expression of pairs of T-cell markers (CD3 and CD8, CD3 and CD45RO or CD8 and CD45RO) (Pages et al, 2009), may be more prognostic than histopathologic TNM stage for patients with stage I– III disease (Mlecnik et al, 2011), and is currently undergoing international validation with a view to its incorporation into routine histopathologic practice (Galon et al, 2012). "
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    ABSTRACT: Background: Foxp3(+) regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. Methods: Foxp3(+), CD3(+), CD4(+), CD8(+) and IL-17(+) cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. Results: Stromal Foxp3(+) cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3(+) cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3(+) cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. Conclusions: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.British Journal of Cancer advance online publication 8 December 2015. doi:10.1038/bjc.2015.427 www.bjcancer.com.
    Preview · Article · Dec 2015 · British Journal of Cancer
    • "However, host immunity in most patients with CRC does not develop a satisfactory antitumor immune response, pointing to the existence of, the prognostic significance of Treg cells in CRC remains controver- sial[15]. Although a number of studies have demonstrated a link between high density of Tregs and TNM stage[13,14]or worse out- comes[10], other studies failed to confirm this relationship[1,16]. Most current studies have found that high density of FoxP3+ Tregs is strongly associated with better outcomes[11,171819. "
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    ABSTRACT: Objectives: T regulatory cells (Tregs) play a critical important role for the occurrence and development of human tumors. Most human colorectal cancers (CRCs) develop from the preformed adenomas, this study is therefore designed to evaluate forkhead box P3 (FoxP3)+ Tregs in human colorectal adenomas. Materials and ethods: FoxP3+ Tregs in human colorectal adenomas were evaluated with immunohistochemistry (IHC) and real-time PCR, and compared to CRCs and normal tissues. In addition, the change of Treg immunosuppressive cytokine interleukin (IL)-10 was examined with IHC and real-time PCR. Results: increased FoxP3+Tregs were observed in the adenomatous stroma/epithelium and the density in colorectal adenomas, which was similar to that in the CRCs, significantly increased as compared to normal tissues. Numerous IL-10+cells were observed in the adenomatous stroma, but not in adenomatous epithelium, as compared with the controls. The density grading score of IL-10+ cells in the adenomas confirmed an increased density of IL-10+cells in the adenomatous/CRC stroma. Double IHCs with CD4/CD25 and IL-10/FoxP3 antibodies confirmed above observations and revealed that IL-10 was at least partially released from increased Tregs. Quantitative real-time PCR results confirmed that the expression levels of FoxP3 and IL-10 mRNAs in the adenomas were increased, which equivalent to that in the CRCs. Conclusion: accumulation of FoxP3+ Tregs in the tumor microenvironment is an early event along the adenoma-carcinoma sequence, and might play a role in the regulation of host immune response to the initiation of CRC.
    No preview · Article · Dec 2015 · Pathology - Research and Practice
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    • "HLA-G is rarely found in healthy tissues, but is frequently observed in tumors [16]. Third, immune reactivity can become suppressed by the attraction of immunosuppressive regulatory T cells (Tregs) into the tumor microenvironment [17,18]. "
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    ABSTRACT: Background Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumorigenesis. The goal of this study was to establish distinct patterns that reflect a rectal tumors’ immune-phenotype and to determine their relation to patient outcome. Methods The study population consisted of 495 Stage I-IV non-preoperatively treated rectal cancer patients of which a tissue micro array (TMA) was available. Sections of this TMA were immunohistochemically stained and quantified for presence of Foxp3+ cells (Tregs) and tumor expression of HLA Class I and non-classical HLA-E and HLA-G. All markers were, separate and combined, analyzed for clinical prognostic value. Results Expression of HLA class I (DFS HR 0.637 (0.458-0.886), p = 0.013), Foxp3+ infiltration above median (OS HR 0.637 (0.500-0.813), p < 0.001 and DFS HR 0.624 (0.491-0.793), p < 0.001) and expression of HLA-G (DFS HR 0.753 (0.574-0.989), p = 0.042) were related to a better clinical prognosis. When these markers were combined, patients with 2 or 3 markers associated with poor prognosis (loss of HLA Class I, Foxp3+ below median, and weak HLA-G expression), showed a significantly worse survival (OS and DFS p < 0.001). This immune-phenotype was an independent predictor for DFS (HR 1.56 (1.14-2.14), p = 0.019). Conclusions In conclusion, rectal tumors showing loss of HLA class I expression, Foxp3+ infiltration below median and weak HLA-G expression were related to a worse OS and DFS. Combining these immune markers lead to the creation of tumor immune-phenotypes , which related to patient outcome and were significant independent clinical prognostic markers in rectal cancer.
    Full-text · Article · Jul 2014 · BMC Cancer
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