Indoleamine 2, 3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells. (1st September 2018)

• Record Type: Journal Article
• Authors: Li, Ailin; Barsoumian, Hampartsoum B.; Schoenhals, Jonathan E.; Cushman, Taylor R.; Caetano, Mauricio S.; Wang, Xiaohong; Valdecanas, David R.; Niknam, Sharareh; Younes, Ahmed I.; Li, Guang; Woodward, Wendy A.; Cortez, Maria Angelica; Welsh, James W.
• Is Part Of: Cancer letters. Volume 431(2018)
• Page Start: 54
• Page End: 63
• Publication Date: 2018-09-01
• Subjects: IDO1 -- Anti-PD1 resistance -- Lung cancer -- Immunotherapy -- Myeloid-derived suppressor cells; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.05.005
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Indoleamine 2, 3-dioxygenase 1 (IDO1), 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 IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80 + Gr1 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, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy. Highlights: Anti-PD1 resistance in lung cancer is associated with activation and accumulation of IDO1-expressing F4/80 + Gr1 int CD11b + - MDSCs. Inhibiting IDO1 decreased IDO1 expression and suppressed the activation and accumulation of F4/80 + Gr1 int CD11b + - MDSCs. The IDO1 inhibitor INCB023843 reactivated T cells and antitumor immune responses in anti-PD1-resistant lung tumors.