Preoperative treatment with a non-steroidal anti-inflammatory drug (NSAID) increases tumor tissue infiltration of seemingly activated immune cells in colorectal cancer.

• This study evaluates HLA gene expression and tumor infiltration by B-cells, macrophages, dendritic cells, T-helper and cytotoxic T-lymphocytes in response to short-term preoperative treatment with cyclooxygenase inhibitors. Patients with colorectal carcinoma were randomized to receive oral NSAID (indomethacin or celebrex) for three days preoperatively; controls received esomeprazol. Peroperative tumor biopsies and normal colon tissue were analyzed by microarray, quantitative PCR and immunohistochemistry. Efficacy of short-term systemic NSAID treatment was confirmed by measurement of PGE2 production in blood monocytes from healthy volunteers. NSAID treatment upregulated genes at the MHC locus on chromosome 6p21 in tumor tissue, but not in normal colon tissue, from the same patient. 23 of the 100 most upregulated genes belonged to MHC class II. HLA-DM, -DO (peptide loading), HLA-DP, -DQ, -DR (antigen presentation), granzyme B, H, perforin and FCGR3A (CD16) (cytotoxicity) displayed increased expression, as did CD8, a marker of cytotoxic T-lymphocytes, while HLA-A and -C expression were not increased by NSAID treatment. MHC II protein (HLA-DP, -DQ, -DR) levels and infiltration by CD4+ T-helper cells of tumor stroma increased upon NSAID treatment, while CD8+ cytotoxic T-lymphocytes increased in both tumor stroma and epithelium. Molecules associated with immunosuppressive T regulatory cells (FOXP3, IL-10) were significantly decreased in indomethacin-exposed tumors. Standard oral administration of NSAID three days preoperatively was enough to increase tumor infiltration by seemingly activated immune cells. These findings agree with previous information that high prostanoid activities in colorectal cancer increase the risk for reduced disease-specific survival following tumor resection.

Nyckelord

Adenocarcinoma

drug therapy

immunology

pathology

surgery

Aged

Aged

80 and over

Anti-Inflammatory Agents

Non-Steroidal

pharmacology

therapeutic use

Cell Movement

drug effects

Colorectal Neoplasms

drug therapy

immunology

pathology

surgery

Cyclooxygenase 2 Inhibitors

pharmacology

therapeutic use

Cyclooxygenase Inhibitors

pharmacology

therapeutic use

Dendritic Cells

drug effects

immunology

Female

Gene Expression Profiling

Gene Expression Regulation

Neoplastic

drug effects

HLA-D Antigens

biosynthesis

genetics

Humans

Indomethacin

pharmacology

therapeutic use

Lymphocyte Subsets

drug effects

immunology

Lymphocytes

Tumor-Infiltrating

drug effects

Macrophages

drug effects

immunology

Male

Middle Aged

Neoplasm Proteins

biosynthesis

genetics

Omeprazole

therapeutic use

Premedication

Preoperative Care

Pyrazoles

pharmacology

therapeutic use

Sulfonamides

pharmacology

therapeutic use

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