In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer

Christoph Loddenkemper,Eckhard Thiel,Michel Noutsias,Dirk Nagorsen,Martin Schernus,Harald Stein

doi:10.1186/1479-5876-4-52

Christoph Loddenkemper, Eckhard Thiel + Show 4 more

Open Access

https://doi.org/10.1186/1479-5876-4-52

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Abstract

The immune system spontaneously responds to tumor-associated antigens in peripheral blood of colorectal cancer (CRC) patients. Regulatory T cells (Treg) are suspected of influencing the interaction between the tumor and immune system and thus the course of malignant diseases. However, the function of Tregs in the development of T cell responses and on the clinical course of CRC is not clear. We analyzed Treg infiltration (FOXP3 staining) in situ in 40 CRC patients and investigated whether there is a correlation to disease stage, systemic T cell response, and survival. Treg infiltration was significantly higher in CRC than in healthy colon. Stromal Treg infiltration was significantly higher than epithelial infiltration in CRC. Furthermore, Treg infiltration in the tumor was significantly higher in limited disease than in metastatic CRC. The average Treg infiltration rate in the tumor was non-significantly higher in patients without systemic TAA-specific T cell response. Survival did not differ between patients with high Treg infiltration and those with low Treg infiltration. In conclusion, a direct link between Treg infiltration in the tumor and the development of a systemic T cell response in CRC cannot be proven. However, local Treg infiltration was significantly higher in limited disease, in which a systemic TAA-directed T cell responses is less frequently observed.

Highlights

In the last years, immunotherapy of malignant diseases and the understanding of underlying mechanisms have made rapid progress despite limited clinical response [1]
The aim of our study was to analyze the infiltration of Colorectal cancer (CRC) by forkhead box P3 (FOXP3)-positive regulatory T cell (Treg) in situ and to investigate whether there is a correlation to disease stage, systemic tumor-associated antigens (TAA)-specific T cell response, and survival of CRC patients
CD8+ T cell infiltration has been described as a positive prognostic factor in CRC [32,33,34,35,36,37], we examined CD8 T cell infiltration in relation to Treg frequency, disease stage and survival

Summary

Introduction

Immunotherapy of malignant diseases and the understanding of underlying mechanisms have made rapid progress despite limited clinical response [1]. T cells directed against tumor antigens are believed to play a crucial role in mediating anti-tumor effects. Spontaneous T cell responses against tumor antigens have been described in a variety of malignant diseases [2]. The colon is considered a rather tolerogenic organ, spontaneous T cell responses against several tumor-associated antigens (TAA) have been detected in the peripheral blood of CRC patients, in metastatic disease [3,4]. Patients with peripheral TAA-directed T cell response showed no benefit in a first survival analysis with a limited number of CRC patients [5].

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