論文

査読有り 国際誌
2019年4月

Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade.

Oral oncology
  • Hidetake Tachinami
  • ,
  • Naoto Nishii
  • ,
  • Yulong Xia
  • ,
  • Yoshihisa Kashima
  • ,
  • Tatsukuni Ohno
  • ,
  • Shigenori Nagai
  • ,
  • Lixin Li
  • ,
  • Walter Lau
  • ,
  • Kei Tomihara
  • ,
  • Makoto Noguchi
  • ,
  • Miyuki Azuma

91
開始ページ
21
終了ページ
28
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.oraloncology.2019.02.014

OBJECTIVES: The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models. MATERIALS AND METHODS: TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+ cells. RESULTS: More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+ cells. A major fraction of NR-S1 CD11b+ cells was Ly6GhighLy6Clow-negaF4/80- tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+ cells were Ly6GlowLy6C-F4/80+ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors. CONCLUSIONS: NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+ myeloid cells may influence the efficacy of immunotherapeutic agents.

リンク情報
DOI
https://doi.org/10.1016/j.oraloncology.2019.02.014
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30926058

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