Blockade of CCL2 expression overcomes intrinsic PD-1/PD-L1 inhibitor-resistance in transglutaminase 2-induced PD-L1 positive triple negative breast cancer
- Authors
- Choi, Junyoung; Lee, Hee Jin; Yoon, Shinkyo; Ryu, Hyun-Min; Lee, Eunjin; Jo, Yujin; Seo, Seyoung; Kim, Deokhoon; Lee, Chang Hoon; Kim, Wanlim; Ha, Joo Young; Kim, Soo-Youl; Gong, Gyungyub; Jung, Kyung Hae; Park, Sook Ryun; Kim, Sang-We; Park, Kang-Seo; Lee, Dae Ho
- Issue Date
- 2020
- Publisher
- E-CENTURY PUBLISHING CORP
- Keywords
- Transglutaminase 2; TNBC; PD-1; PD-L1; drug resistance
- Citation
- AMERICAN JOURNAL OF CANCER RESEARCH, v.10, no.9, pp 2878 - +
- Journal Title
- AMERICAN JOURNAL OF CANCER RESEARCH
- Volume
- 10
- Number
- 9
- Start Page
- 2878
- End Page
- +
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/63619
- ISSN
- 2156-6976
2156-6976
- Abstract
- Anti-PD-1/PD-L1 immunotherapy, as a treatment for many tumors, has shown good efficacy. However, responses to immunotherapy did not always occur or last long., i.e. primary or acquired resistance, even tumors were PD-L1 positive. Several oncogenic pathways, including PI3K/AKT activation by PTEN loss and NF-kappa B activation, induce PD-L1 expression and PD-L1 inhibitor-resistance. They also induce expression of CCL2, an inhibitory chemokine that blocks T cell tracking into the tumor by binding to CCR2 on the T cell surface. In this study, we showed that transglutaminase 2 (TG2), a post-translational modification enzyme, induced ubiquitin-proteasome dependent degradation of tumor suppressors including PTEN and I kappa B alpha by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-kappa B activation. It also induced PD-L1 inhibitor-resistance because CCL2 was expressed despite increased PD-L1, which was blocked by PD-L1 inhibitor. We also revealed that inhibition of TG2, instead of PD-L1, restored T cell-dependent killing effect by blocking expression of both PD-L1 and CCL2 in PD-L1(+) triple negative breast cancer (TNBC) cells. In addition, the TG2-expressingTN BC patient group showed higher PD-L1 expression incidence than did the TG2-negative TNBC patient group. In conclusion, TG2 induces primary PD-1/PD-L1 inhibitor-resistance by inducing CCL2 expression. TG2 blockade can be utilized as an excellent therapeutic strategy to overcome PD-L1 inhibitor-resistance in PD-L1(+) TNBC patients. Our study suggested that PD-L1 expression alone might not always be a predictive biomarker for PD-L1(+)TNBC, but TG2 could be a useful predictive marker to select PD-L1 inhibitor-resistant TNBC patients.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - College of Medicine > College of Medicine > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.