TY - JOUR
T1 - Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance
AU - Hennequart, Marc
AU - Pilotte, Luc
AU - Cane, Stefania
AU - Hoffmann, Delia
AU - Stroobant, Vincent
AU - De Plaen, Etienne
AU - Van Den Eynde, Benoît J.
N1 - Funding Information:
We thank Guy Warnier, Gilles Gaudray, Julien Gossiaux, and Laurent Her-mans for production of NOD/Scid/Il-2rg/ (NSG) mice; Sophie Lucas, Catherine Uyttenhove, and Stephanie Lienart for advice on the NSG experiment; Celine Bugli for statistical advice; Pierre van der Bruggen and Pierre Coulie for critical comments; and Auriane Sibille for editorial assistance. This work was supported by Ludwig Cancer Research, Walloon Excellence in Life Sciences and Biotechnology (WELBIO, Belgium), FNRS-Televie (Belgium), Foundation Against Cancer (Belgium), de Duve Institute and Universite catholique de Louvain (Belgium). M. Hennequart was supported by FNRS-Televie (Grant number: 7.4590.15), L. Pilotte by de Duve Institute, S. Cane by FNRS-Televie (Grant number: 7.4538.14), D. Hoffmann by FRIA (Grant number: 1.E082.14), and V. Stroobant, E. De Plaen, and B.J. Van den Eynde by the Ludwig Institute for Cancer Research.
Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. COX-2 expression itself depends on the MAPK pathway, which therefore indirectly controls IDO1 expression. Most of these tumors carry PI3K or MAPK oncogenic mutations, which may favor constitutive IDO1 expression. Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3þ and CD8þ cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy.
AB - Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. COX-2 expression itself depends on the MAPK pathway, which therefore indirectly controls IDO1 expression. Most of these tumors carry PI3K or MAPK oncogenic mutations, which may favor constitutive IDO1 expression. Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3þ and CD8þ cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy.
UR - http://www.scopus.com/inward/record.url?scp=85026737480&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-16-0400
DO - 10.1158/2326-6066.CIR-16-0400
M3 - Article
C2 - 28765120
AN - SCOPUS:85026737480
SN - 2326-6066
VL - 5
SP - 695
EP - 709
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -