Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells

被引:54
作者
Li, Ailin [1 ]
Barsoumian, Hampartsoum B. [2 ]
Schoenhals, Jonathan E. [2 ]
Cushman, Taylor R. [2 ]
Caetano, Mauricio S. [2 ]
Wang, Xiaohong [3 ]
Valdecanas, David R. [3 ]
Niknam, Sharareh [2 ]
Younes, Ahmed, I [2 ]
Li, Guang [1 ]
Woodward, Wendy A. [2 ]
CorteZ, Maria Angelica [3 ]
Welsh, James W. [2 ]
机构
[1] China Med Univ, Dept Radiat Oncol, Hosp 1, Shenyang, Liaoning, Peoples R China
[2] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Unit 97,1515 Holcombe Blvd, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA
基金
中国国家自然科学基金;
关键词
IDO1; Anti-PD1; resistance; Lung cancer; Immunotherapy; Myeloid-derived suppressor cells; ARYL-HYDROCARBON RECEPTOR; IDO EXPRESSION; T-CELLS; TRYPTOPHAN DEGRADATION; RESISTANCE MECHANISM; CHECKPOINT BLOCKADE; COLORECTAL-CANCER; IMMUNE ACTIVATION; PD-1; BLOCKADE; NIVOLUMAB;
D O I
10.1016/j.canlet.2018.05.005
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Indoleamine 2,3-dioxygenase 1 (ID01), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDOL inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDOL was expressed at higher levels in F4/80(+)Grl(int)CD11b(+) myeloid derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8(+) T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDOL inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.
引用
收藏
页码:54 / 63
页数:10
相关论文
共 40 条
[1]   Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer [J].
Astigiano, S ;
Morandi, B ;
Costa, R ;
Mastracci, L ;
D'Agostino, A ;
Ratto, GB ;
Melioli, G ;
Frumento, G .
NEOPLASIA, 2005, 7 (04) :390-396
[2]   Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer [J].
Borghaei, H. ;
Paz-Ares, L. ;
Horn, L. ;
Spigel, D. R. ;
Steins, M. ;
Ready, N. E. ;
Chow, L. Q. ;
Vokes, E. E. ;
Felip, E. ;
Holgado, E. ;
Barlesi, F. ;
Kohlhaeufl, M. ;
Arrieta, O. ;
Burgio, M. A. ;
Fayette, J. ;
Lena, H. ;
Poddubskaya, E. ;
Gerber, D. E. ;
Gettinger, S. N. ;
Rudin, C. M. ;
Rizvi, N. ;
Crino, L. ;
Blumenschein, G. R. ;
Antonia, S. J. ;
Dorange, C. ;
Harbison, C. T. ;
Finckenstein, F. Graf ;
Brahmer, J. R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (17) :1627-1639
[3]   Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer [J].
Brahmer, Julie ;
Reckamp, Karen L. ;
Baas, Paul ;
Crino, Lucio ;
Eberhardt, Wilfried E. E. ;
Poddubskaya, Elena ;
Antonia, Scott ;
Pluzanski, Adam ;
Vokes, Everett E. ;
Holgado, Esther ;
Waterhouse, David ;
Ready, Neal ;
Gainor, Justin ;
Aren Frontera, Osvaldo ;
Havel, Libor ;
Steins, Martin ;
Garassino, Marina C. ;
Aerts, Joachim G. ;
Domine, Manuel ;
Paz-Ares, Luis ;
Reck, Martin ;
Baudelet, Christine ;
Harbison, Christopher T. ;
Lestini, Brian ;
Spigel, David R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (02) :123-135
[4]   Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer:: Effect on tumor-infiltrating T cells [J].
Brandacher, G ;
Perathoner, A ;
Ladurner, R ;
Schneeberger, S ;
Obrist, P ;
Winkler, C ;
Werner, ER ;
Werner-Felmayer, G ;
Weiss, HG ;
Göbel, G ;
Margreiter, R ;
Königsrainer, A ;
Fuchs, D ;
Amberger, A .
CLINICAL CANCER RESEARCH, 2006, 12 (04) :1144-1151
[5]   Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF [J].
Dolcetti, Luigi ;
Peranzoni, Elisa ;
Ugel, Stefano ;
Marigo, Ilaria ;
Fernandez Gomez, Audry ;
Mesa, Circe ;
Geilich, Markus ;
Winkels, Gregor ;
Traggiai, Elisabetta ;
Casati, Anna ;
Grassi, Fabio ;
Bronte, Vincenzo .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2010, 40 (01) :22-35
[6]   Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression [J].
Gibbons, Don L. ;
Lin, Wei ;
Creighton, Chad J. ;
Rizvi, Zain H. ;
Gregory, Philip A. ;
Goodall, Gregory J. ;
Thilaganathan, Nishan ;
Du, Liqin ;
Zhang, Yiqun ;
Pertsemlidis, Alexander ;
Kurie, Jonathan M. .
GENES & DEVELOPMENT, 2009, 23 (18) :2140-2151
[7]   Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner [J].
Holmgaard, Rikke B. ;
Zamarin, Dmitriy ;
Li, Yanyun ;
Gasmi, Billel ;
Munn, David H. ;
Allison, James P. ;
Merghoub, Taha ;
Wolchok, Jedd D. .
CELL REPORTS, 2015, 13 (02) :412-424
[8]   Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 [J].
Holmgaard, Rikke B. ;
Zamarin, Dmitriy ;
Munn, David H. ;
Wolchok, Jedd D. ;
Allison, James P. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2013, 210 (07) :1389-1402
[9]   Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer [J].
Huang, A ;
Fuchs, D ;
Widner, B ;
Glover, C ;
Henderson, DC ;
Allen-Mersh, TG .
BRITISH JOURNAL OF CANCER, 2002, 86 (11) :1691-1696
[10]   Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation [J].
Hwu, P ;
Du, MX ;
Lapointe, R ;
Do, M ;
Taylor, MW ;
Young, HA .
JOURNAL OF IMMUNOLOGY, 2000, 164 (07) :3596-3599