| Autor: |
Junyoung, Choi, Hee Jin, Lee, Shinkyo, Yoon, Hyun-Min, Ryu, Eunjin, Lee, Yujin, Jo, Seyoung, Seo, Deokhoon, Kim, Chang Hoon, Lee, Wanlim, Kim, Joo Young, Ha, Soo-Youl, Kim, Gyungyub, Gong, Kyung Hae, Jung, Sook Ryun, Park, Sang-We, Kim, Kang-Seo, Park, Dae Ho, Lee |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Am J Cancer Res |
| ISSN: |
2156-6976 |
| Popis: |
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-κB 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 IκBα by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-κB 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-expressing TNBC 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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