COX-2 Helps Cancer Cells Avoid Immune Attack

Researchers studying how cancer cells avoid attack by the immune system have found that overexpression of the gene for cyclooxygenase-2 (COX-2) by certain tumors prevents dendritic cells from staging a Th1 inflammatory response and causes them to shift into a Tr1 immunosuppressive mode.

Normally, dendritic cells induce the production of interleukin-12 (IL-12), which prompts CD4+ T lymphocytes to launch a T helper type 1 (Th1) inflammatory response. However, in the current study published in the October 1, 2004, issue of the Journal of Immunology, investigators at the Maxine Dunitz Neurosurgical Institute of Cedars-Sinai Medical Center (Los Angeles, CA, USA; www.cedars-sinai.edu/mdnsi) reported that overexpression of COX-2 modified dendritic cell behavior.

When dendritic cells were exposed to cancer cells whose COX-2 overexpression caused elevated levels of prostaglandin E2, the dendritic cells prompted the overproduction of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) instead of inducing the production of interleukin-12 (IL-12). These two substances triggered a Trl regulatory response that caused lymphocytes to be tolerant of tumor cell antigens.

Senior author Dr. John S. Yu, co-director of the comprehensive brain tumor program at the Maxine Dunitz Neurosugical Institute, said, "COX-2 expression by tumors may make them invisible to the immune system. By using COX-2 inhibitors, these tumors may become more detectable and therefore more vulnerable to destruction by the immune system. One of the intriguing findings was that helper cells isolated from the bloodstream of a glioblastoma patient predominantly displayed a regulatory response against the patient's glioma cells. This points to the existence of an underlying regulatory bias in the circulating T cells of patients with malignant glioma.”




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Maxine Dunitz Neurosurgical Institute