論文

査読有り 国際誌
2018年7月17日

Induction of oligoclonal CD8 T cell responses against pulmonary metastatic cancer by a phospholipid-conjugated TLR7 agonist.

Proceedings of the National Academy of Sciences of the United States of America
  • Tadashi Hosoya
  • ,
  • Fumi Sato-Kaneko
  • ,
  • Alast Ahmadi
  • ,
  • Shiyin Yao
  • ,
  • Fitzgerald Lao
  • ,
  • Kazutaka Kitaura
  • ,
  • Takaji Matsutani
  • ,
  • Dennis A Carson
  • ,
  • Tomoko Hayashi

担当区分
筆頭著者
115
29
開始ページ
E6836-E6844
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1073/pnas.1803281115

Recent advances in cancer immunotherapy have improved patient survival. However, only a minority of patients with pulmonary metastatic disease respond to treatment with checkpoint inhibitors. As an alternate approach, we have tested the ability of systemically administered 1V270, a toll-like receptor 7 (TLR7) agonist conjugated to a phospholipid, to inhibit lung metastases in two variant murine 4T1 breast cancer models, as well as in B16 melanoma, and Lewis lung carcinoma models. In the 4T1 breast cancer models, 1V270 therapy inhibited lung metastases if given up to a week after primary tumor initiation. The treatment protocol was facilitated by the minimal toxic effects exerted by the phospholipid TLR7 agonist compared with the unconjugated agonist. 1V270 exhibited a wide therapeutic window and minimal off-target receptor binding. The 1V270 therapy inhibited colonization by tumor cells in the lungs in an NK cell dependent manner. Additional experiments revealed that single administration of 1V270 led to tumor-specific CD8+ cell-dependent adaptive immune responses that suppressed late-stage metastatic tumor growth in the lungs. T cell receptor (TCR) repertoire analyses showed that 1V270 therapy induced oligoclonal T cells in the lungs and mediastinal lymph nodes. Different animals displayed commonly shared TCR clones following 1V270 therapy. Intranasal administration of 1V270 also suppressed lung metastasis and induced tumor-specific adaptive immune responses. These results indicate that systemic 1V270 therapy can induce tumor-specific cytotoxic T cell responses to pulmonary metastatic cancers and that TCR repertoire analyses can be used to monitor, and to predict, the response to therapy.

リンク情報
DOI
https://doi.org/10.1073/pnas.1803281115
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29967183
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055176

エクスポート
BibTeX RIS