2. Academic Validation
  3. Blockade of CCL2 expression overcomes intrinsic PD-1/PD-L1 inhibitor-resistance in transglutaminase 2-induced PD-L1 positive triple negative breast cancer

Blockade of CCL2 expression overcomes intrinsic PD-1/PD-L1 inhibitor-resistance in transglutaminase 2-induced PD-L1 positive triple negative breast cancer

  • Am J Cancer Res. 2020 Sep 1;10(9):2878-2894.
Junyoung Choi 1 2,  Hee Jin Lee 3,  Shinkyo Yoon 1,  Hyun-Min Ryu 1 2,  Eunjin Lee 1 2,  Yujin Jo 1,  Seyoung Seo 1,  Deokhoon Kim 4,  Chang Hoon Lee 5,  Wanlim Kim 6,  Joo Young Ha 7,  Soo-Youl Kim 8,  Gyungyub Gong 3,  Kyung Hae Jung 1,  Sook Ryun Park 1,  Sang-We Kim 1,  Kang-Seo Park 1 2,  Dae Ho Lee 1
Affiliations

Affiliations

  • 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
  • 2 Department of Biomedical Sciences, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
  • 3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
  • 4 Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center Seoul 05505, Republic of Korea.
  • 5 Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT) Daejeon, Republic of Korea.
  • 6 Department of Orthopaedic Surgery, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
  • 7 Division of Hematology/Medical Oncology, Department of Internal Medicine, Chung-Ang University College of Medicine Seoul 06973, Republic of Korea.
  • 8 Tumor Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center Goyang 10408, Republic of Korea.
PMID: 33042623
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-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.

Keywords

PD-1; PD-L1; TNBC; Transglutaminase 2; drug resistance.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12337
    99.93%, Glutaminase Inhibitor