Tumor cell-induced deactivation of human monocytes.
Although blood monocytes exhibit significant cytotoxic activity against tumor cells, the function of tumor infiltrating macrophages (TIM) is depressed in cancer patients. This study addresses the question of how the antitumor response of human monocytes, assessed by production of cytokines (tumor necrosis factor alpha, TNF; IL-10; IL-12p40) and cytotoxicity, is altered by exposure to cancer cells. Tumor cell--pre-exposed monocytes restimulated with tumor cells showed significantly decreased production of TNF, IL-12, increased IL-10 (mRNA and release) and inhibition of IL-1 receptor-associated kinase-1 (IRAK-1) expression. This down-regulation of cytokine production was selective, as the response of pre-exposed monocytes to lipopolysaccharide (LPS) was unaffected. Treatment of tumor cell--pre-exposed monocytes with hyaluronidase (HAase) improved their depressed production of TNF, while HAase-treated cancer cells did not cause monocyte dysfunction. The response of hyaluronan (HA)--pre-exposed monocytes to stimulation with tumor cells was also inhibited. Cytotoxic activity of monocytes pretreated with cancer cells was also decreased. This study shows that tumor cells selectively deactivate monocytes and suggests that tumor cell-derived HA by blocking CD44 on monocytes inhibits their antitumor response. These observations may provide some explanation for the depressed function of TIM in human malignancy.
Mytar
Bozenna
B
Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Cracow, Poland.
Wołoszyn
Maria
M
Szatanek
Rafał
R
Baj-Krzyworzeka
Monika
M
Siedlar
Maciej
M
Ruggiero
Irena
I
Wieckiewicz
Jerzy
J
Zembala
Marek
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D009439:Neuraminidase / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018960:Hyaluronan Receptors; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D021122:Protein Subunits; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D006820:Hyaluronic Acid; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D009439:Neuraminidase; D006821:Hyaluronoglucosaminidase