Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Dec 22;113(12):1677-86.
doi: 10.1038/bjc.2015.427. Epub 2015 Dec 8.

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

M J McCoy  1   2 , C Hemmings  3   4 , T J Miller  1   4 , S J Austin  1 , M K Bulsara  5 , N Zeps  1   4 , A K Nowak  2   6 , R A Lake  2 , C F Platell  1   4
Affiliations

Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

M J McCoy et al. Br J Cancer. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Identification of T-cell subsets. (A) Representative immunohistochemical staining of stromal cores for Foxp3 (top left), CD3 (top centre), CD4 (top right), CD8 (bottom left), IL-17 (bottom centre) and multiplex detection of Foxp3 (green), CD4 (brown) and CD8 (pink) (bottom right). Arrows indicate CD4+Foxp3+ cells. Scale bar, 50 μm. (B) Frequencies of Foxp3+, CD4+, CD8+ and IL-17+ cells in tumour (Dworak 1–3 patients only), stroma and normal cores. Line at median. *P<0.05, **P<0.01, ***P<0.001.
Figure 2
Figure 2
Low stromal Foxp3+ cell density is associated with response to CRT. (A) Stromal Foxp3+ cell density by Dworak grade (P=0.0006; general linear model). Circles represent outliers using Tukey's method (> the 75th percentile plus 1.5 times the interquartile range). (B) Low vs high stromal Foxp3+ cell density (split at the median value) by pCR (P=0.0005; logistic regression). ***P<0.001.
Figure 3
Figure 3
Survival by Dworak grade and stromal Foxp3+ cell density. Kaplan–Meier estimates for cancer-specific and recurrence-free survival by (A and B) Dworak grade and (C and D) stromal Foxp3+ cell density. Groups compared using the log-rank test. *Test for trend.
See this image and copyright information in PMC

References

    1. ACN (Australian Cancer Network) Colorectal Cancer Guidelines Revision Committee (2005) Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer. The Cancer Council Australia and Australian Cancer Network: Sydney.
    1. Agarwal A, Chang GJ, Hu CY, Taggart M, Rashid A, Park IJ, You YN, Das P, Krishnan S, Crane CH, Rodriguez-Bigas M, Skibber J, Ellis L, Eng C, Kopetz S, Maru DM (2013) Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy. Cancer 119(24): 4231–4241. - PMC - PubMed
    1. Anitei MG, Zeitoun G, Mlecnik B, Marliot F, Haicheur N, Todosi AM, Kirilovsky A, Lagorce C, Bindea G, Ferariu D, Danciu M, Bruneval P, Scripcariu V, Chevallier JM, Zinzindohoue F, Berger A, Galon J, Pages F (2014) Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin Cancer Res 20(7): 1891–1899. - PubMed
    1. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9): 1050–1059. - PubMed
    1. Barnes MJ, Powrie F (2009) Regulatory T cells reinforce intestinal homeostasis. Immunity 31(3): 401–411. - PubMed

Publication types

Substances