Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.
Liu
Xiangdong
X
Incyte Corporation, Wilmington, DE, USA.
Shin
Niu
N
Koblish
Holly K
HK
Yang
Gengjie
G
Wang
Qian
Q
Wang
Kathy
K
Leffet
Lynn
L
Hansbury
Michael J
MJ
Thomas
Beth
B
Rupar
Mark
M
Waeltz
Paul
P
Bowman
Kevin J
KJ
Polam
Padmaja
P
Sparks
Richard B
RB
Yue
Eddy W
EW
Li
Yanlong
Y
Wynn
Richard
R
Fridman
Jordan S
JS
Burn
Timothy C
TC
Combs
Andrew P
AP
Newton
Robert C
RC
Scherle
Peggy A
PA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D014366:Tryptophan Oxygenase / Q000276:immunology / Q000378:metabolism
D051940:B7-2 Antigen; C497964:CD86 protein, human; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014366:Tryptophan Oxygenase