Daniëlle Krijgsman1, Jessica Roelands2, Morten N Andersen3, Cornelia H L A Wieringa1, Rob A E M Tollenaar1, Wouter Hendrickx4, Davide Bedognetti4, Marianne Hokland5, Peter J K Kuppen6. 1. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. 2. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Cancer Research Department, Research Branch, Sidra Medicine, Doha, Qatar. 3. Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. 4. Cancer Research Department, Research Branch, Sidra Medicine, Doha, Qatar. 5. Department of Biomedicine, Aarhus University, Aarhus, Denmark. 6. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: P.J.K.Kuppen@lumc.nl.
Abstract
INTRODUCTION: Natural killer (NK) cells and natural killer T (NKT) cells are implicated in the development and progression of colorectal cancer (CRC). Tumor cells express NK cell receptor ligands that modulate their function. This study aimed to investigate the expression of such ligands in CRC in relation to the phenotype of circulating NK- and NKT cells, and clinical outcome. METHODS: Primary tumor tissues were analyzed for protein expression of NK cell ligands using immunohistochemistry with automated image analysis in a cohort of 78 CRC patients. For 24 of the 78 patients, RNA expression of NK cell ligands was analyzed in primary tumor tissue using RNA sequencing. Receptor expression on circulating NK- and NKT cells was previously measured by us in 71 of the 78 patients using flow cytometry. RESULTS: High Proliferating Cell Nuclear Antigen (PCNA) protein expression in the primary tumor associated with shorter disease-free survival (DFS) of CRC patients (P = 0.026). A trend was observed towards shorter DFS in CRC patients with above-median galectin-3 protein expression in the primary tumor (P = 0.055). High protein expression of galectin-3, CD1d, and human leukocyte antigen (HLA) class I, and high RNA expression of UL16-binding protein (ULBP)-1, -2, and -5, and HLA-E in the tumor tissue correlated with low expression of the corresponding receptors on circulating NK- or NKT cells (P < 0.05). CONCLUSIONS: Galectin-3 and PCNA expression in the primary tumor may be prognostic biomarkers in CRC patients. Furthermore, our results suggest that NK cell receptor ligands expressed by tumor cells may modulate the phenotype of circulating NK- and NKT cells, and facilitate immune escape of metastasizing cells.
INTRODUCTION: Natural killer (NK) cells and natural killer T (NKT) cells are implicated in the development and progression of colorectal cancer (CRC). Tumor cells express NK cell receptor ligands that modulate their function. This study aimed to investigate the expression of such ligands in CRC in relation to the phenotype of circulating NK- and NKT cells, and clinical outcome. METHODS:Primary tumor tissues were analyzed for protein expression of NK cell ligands using immunohistochemistry with automated image analysis in a cohort of 78 CRCpatients. For 24 of the 78 patients, RNA expression of NK cell ligands was analyzed in primary tumor tissue using RNA sequencing. Receptor expression on circulating NK- and NKT cells was previously measured by us in 71 of the 78 patients using flow cytometry. RESULTS: High Proliferating Cell Nuclear Antigen (PCNA) protein expression in the primary tumor associated with shorter disease-free survival (DFS) of CRCpatients (P = 0.026). A trend was observed towards shorter DFS in CRCpatients with above-median galectin-3 protein expression in the primary tumor (P = 0.055). High protein expression of galectin-3, CD1d, and human leukocyte antigen (HLA) class I, and high RNA expression of UL16-binding protein (ULBP)-1, -2, and -5, and HLA-E in the tumor tissue correlated with low expression of the corresponding receptors on circulating NK- or NKT cells (P < 0.05). CONCLUSIONS:Galectin-3 and PCNA expression in the primary tumor may be prognostic biomarkers in CRCpatients. Furthermore, our results suggest that NK cell receptor ligands expressed by tumor cells may modulate the phenotype of circulating NK- and NKT cells, and facilitate immune escape of metastasizing cells.
Authors: Johanna Waidhauser; Pia Nerlinger; Florian Sommer; Sebastian Wolf; Stefan Eser; Phillip Löhr; Andreas Rank; Bruno Märkl Journal: Diagnostics (Basel) Date: 2022-06-07