Klinische Bedeutung und therapeutisches Potential des programmierten Zelltod 1- und 2-Liganden (PDL-1, L-2) für das kolorektale Karzinom

Abstract

The programmed death-1/programmed death ligand (PD-1/PD-L) pathway in T cell activation has been suggested to play an important role in tumor evasion from host immunity. However, despite ample evidence from experimental models data in clinical colorectal tumors are scarce. Thus, we investigated the expression of PD-L1 and PD-L2 in human colorectal cancer to define their clinical significance in patients’ prognosis after surgery and asked for the potential role of PD-1 positive T cells within colorectal tumors. Tissue samples from 116 patients operated between 2001 and 2003 with histologically confirmed colorectal carcinoma were evaluated retrospectively for this study. PD-L1 and PD-L2 gene expression together with protein expression were evaluated and outcome analyses were conducted. The protein and mRNA levels as determined by immunohistochemistry and real time PCR were closely correlated. Multivariate analysis indicated that PD-L expression was an independent prognostic factor for colorectal carcinoma. T cell infiltration was observed in 105 (90.5 %) specimens while 67 (63.8 %) out of 105 specimens contained PD-1 positive T cells. Furthermore, patients with PD-1 positive T cells had significantly more PD-L1 expression in their tumor tissue. Presence of tumor infiltrating PD-1 positive T cells was associated with an advanced tumor stage. In addition, patients with PD-L positive tumor tissue and those with tumor infiltrating PD-1 positive T cells had a significantly poorer prognosis than negative patients This was more pronounced in advanced tumor stages than in early stages. These data suggest that interactions of T cells expressing PD-1 may promote cancer progression through a down-regulation of anti-tumor immunity. The PD-L1 and PD-L2 expression may be a new predictor of prognosis for patients with colorectal carcinoma and provide the rationale for developing novel immunotherapies to target the PD-1/PD-L pathway.