Der Verlust von CD3-zeta in Tumor-infiltrierenden T-Zellen ist ein negativer Prognosemarker für das Kolonkarzinom

Abstract

Introduction: In this study we immunohistochemically evaluated 47 resected tumour specimens of patients with colorectal cancer (N0 and N2 tumours, mean age of patients 66.2 years) as well as 21 resected specimens of patients with liver metastases from colorectal cancer (mean age 64.0 years) for their immunocellular infiltrate. Results: There was no significant difference of the immunocellular infiltrate of N0 and N2 tumours. Within the stroma infiltrates consisted of 30 % of CD4 and 30 % of CD8-cells, about 20 % neutrophils and only 7–14 % NK-cells. All other cells were uncommon (< 5 %) and dendritic cells (DCs) only rarely seen. A similar distribution was seen in liver metastases, though NK-cells were the most common cells seen here (30 %). Within clusters of tumour cells immune cells were less common compared with the stroma, in particular DCs and macrophages (MФs). The amount of neutrophils, CD4- and CD8-cells was significantly larger in colon cancer specimens than in liver metastases (p < 0.05). However, liver metastases revealed significantly more NK-cells and B-cells (p = 0.01). CD3-zeta(ζ) was used as a marker of activation of T-cells. Clusters of tumour cells showed a significant loss of CD3-ζ compared with the stroma (p < 0.05). Also, N2 tumours and liver metastases revealed a CD3-ζ loss when compared to N0 tumours (p = 0.032 and p = 0.001). Remarkably, patients with a high number of lymphocytes expressing large amounts of CD3-ζ showed a significantly better survival (p = 0.001). Interestingly, soluble Fas ligand (sFasL) was significantly more expressed in liver metastases than in N0 tumours (p = 0.001). Conclusions: Patients with metastases revealed a more severe immunosuppression than patients without metastases. This was reflected by a loss of neutrophils and activated lymphocytes. B-cells as part of a Th2-reaction and HLA-unrestricted NK-cells were more commonly found. Professional antigen presenting cells, commonly triggering effective immune reactions were almost absent in most tumours. Increased expression of apoptosis-inducing molecules like sFasL could enhance the local immunosuppression, in particular in metastases. Most importantly, survival of all patients with a loss of activated tumour-infiltrating T-cells was significantly reduced. Therefore, local immunosuppression induced by malignant cells is significantly associated with a poorer prognosis. Identification of these mechanisms may be a first step towards the development of immunotherapies which have to aim at restoring T-cell function as well as activation of antigen presentation.