Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 202, Issue 7, Pages 931-939Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050715
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Funding
- NCI NIH HHS [R01 CA082689, R01 CA 88885, R01 CA107974, R01 CA088885, R01 CA 82689] Funding Source: Medline
- PHS HHS [R01-10655914] Funding Source: Medline
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Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting L-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE(2). Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE(2) receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.
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