Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type I interferon pathway in PD‐L1‐expressing head and neck cancer

Author:

Jang Jeon Yeob12ORCID,Lee Bok‐Soon1ORCID,Huang Mei1,Seo Chorong1,Choi Ji‐Hye3ORCID,Shin Yoo Seob1,Woo Hyun Goo3ORCID,Kim Chul‐Ho14ORCID

Affiliation:

1. Department of Otolaryngology Ajou University School of Medicine Suwon Korea

2. Department of Biomedical Sciences Ajou University Graduate School of Medicine Suwon Korea

3. Department of Physiology Ajou University School of Medicine Suwon Korea

4. Deparment of Molecular Science and Technology Ajou University Suwon Korea

Abstract

Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD‐1) have been proven to be an effective first‐line therapy against programmed cell death 1 ligand 1 (PD‐L1; also known as CD274 molecule)‐expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE‐048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12‐dimethylbenzanthracene into the buccal mucosa. Single‐cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD‐L1‐expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD‐L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB‐induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD‐L1‐expressing HNSCC in the KEYNOTE‐048 trial.

Funder

National Research Foundation of Korea

Publisher

Wiley

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