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YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

Authors
 Dong Kwon Kim  ;  Chun-Bong Synn  ;  Seung Min Yang  ;  Seongsan Kang  ;  Sujeong Baek  ;  Se-Woong Oh  ;  Gyu-Jin Lee  ;  Ho-Woong Kang  ;  Young-Sung Lee  ;  Jong Suk Park  ;  Jae Hwan Kim  ;  Youngseon Byeon  ;  Young Seob Kim  ;  Doo Jae Lee  ;  Hyun-Woo Kim  ;  June Dong Park  ;  Sung Sook Lee  ;  Ji Yun Lee  ;  Jii Bum Lee  ;  Chang Gon Kim  ;  Min Hee Hong  ;  Sun Min Lim  ;  Hey Ryun Kim  ;  Kyoung-Ho Pyo  ;  Byoung Chul Cho 
Citation
 FRONTIERS IN CHEMISTRY, Vol.10 : 998013, 2022-12 
Journal Title
FRONTIERS IN CHEMISTRY
Issue Date
2022-12
Keywords
IDO1 ; colon cancer ; immunotherapy ; kynurenine ; molecule inhibitor ; tryptophan
Abstract
Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1.
Files in This Item:
T202300456.pdf Download
DOI
10.3389/fchem.2022.998013
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Young Seob(김영섭)
Kim, Jae Hwan(김재환)
Kim, Chang Gon(김창곤)
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Byeon, Yeongseon(변영선)
Lee, Jii Bum(이기쁨) ORCID logo https://orcid.org/0000-0001-5608-3157
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/193004
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