Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance

Daisuke Muraoka, Naohiro Seo, Tae Hayashi, Yoshiro Tahara, Keisuke Fujii, Isao Tawara, Yoshihiro Miyahara, Kana Okamori, Hideo Yagita, Seiya Imoto, Rui Yamaguchi, Mitsuhiro Komura, Satoru Miyano, Masahiro Goto, Shin Ichi Sawada, Akira Asai, Hiroaki Ikeda, Kazunari Akiyoshi, Naozumi Harada, Hiroshi Shiku

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition–sensitive and –resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity. We identified antigen presentation by CD11b + F4/80 + tumor–associated macrophages (TAMs) as a key factor correlated with immune resistance. In the resistant tumors, TAMs remained inactive and did not exert antigen-presenting activity. Targeted delivery of a long peptide antigen to TAMs by using a nano-sized hydrogel (nanogel) in the presence of a TLR agonist activated TAMs, induced their antigen-presenting activity, and thereby transformed the resistant tumors into tumors sensitive to adaptive immune responses such as adoptive transfer of tumor-specific T cell receptor–engineered T cells. These results indicate that the status and function of TAMs have a significant impact on tumor immune sensitivity and that manipulation of TAM functions would be an effective approach for improving the efficacy of immunotherapies.

元の言語英語
ページ(範囲)1278-1294
ページ数17
ジャーナルJournal of Clinical Investigation
129
発行部数3
DOI
出版物ステータス出版済み - 3 1 2019

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Macrophages
Antigens
Neoplasms
Adoptive Transfer
T-Lymphocytes
Immunotherapy
Tumor Microenvironment
Hydrogel
Antigen Presentation
Adaptive Immunity
Peptides
Genes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Muraoka, D., Seo, N., Hayashi, T., Tahara, Y., Fujii, K., Tawara, I., ... Shiku, H. (2019). Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance. Journal of Clinical Investigation, 129(3), 1278-1294. https://doi.org/10.1172/JCI97642

Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance. / Muraoka, Daisuke; Seo, Naohiro; Hayashi, Tae; Tahara, Yoshiro; Fujii, Keisuke; Tawara, Isao; Miyahara, Yoshihiro; Okamori, Kana; Yagita, Hideo; Imoto, Seiya; Yamaguchi, Rui; Komura, Mitsuhiro; Miyano, Satoru; Goto, Masahiro; Sawada, Shin Ichi; Asai, Akira; Ikeda, Hiroaki; Akiyoshi, Kazunari; Harada, Naozumi; Shiku, Hiroshi.

:: Journal of Clinical Investigation, 巻 129, 番号 3, 01.03.2019, p. 1278-1294.

研究成果: ジャーナルへの寄稿記事

Muraoka, D, Seo, N, Hayashi, T, Tahara, Y, Fujii, K, Tawara, I, Miyahara, Y, Okamori, K, Yagita, H, Imoto, S, Yamaguchi, R, Komura, M, Miyano, S, Goto, M, Sawada, SI, Asai, A, Ikeda, H, Akiyoshi, K, Harada, N & Shiku, H 2019, 'Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance', Journal of Clinical Investigation, 巻. 129, 番号 3, pp. 1278-1294. https://doi.org/10.1172/JCI97642
Muraoka, Daisuke ; Seo, Naohiro ; Hayashi, Tae ; Tahara, Yoshiro ; Fujii, Keisuke ; Tawara, Isao ; Miyahara, Yoshihiro ; Okamori, Kana ; Yagita, Hideo ; Imoto, Seiya ; Yamaguchi, Rui ; Komura, Mitsuhiro ; Miyano, Satoru ; Goto, Masahiro ; Sawada, Shin Ichi ; Asai, Akira ; Ikeda, Hiroaki ; Akiyoshi, Kazunari ; Harada, Naozumi ; Shiku, Hiroshi. / Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance. :: Journal of Clinical Investigation. 2019 ; 巻 129, 番号 3. pp. 1278-1294.
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abstract = "Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition–sensitive and –resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity. We identified antigen presentation by CD11b + F4/80 + tumor–associated macrophages (TAMs) as a key factor correlated with immune resistance. In the resistant tumors, TAMs remained inactive and did not exert antigen-presenting activity. Targeted delivery of a long peptide antigen to TAMs by using a nano-sized hydrogel (nanogel) in the presence of a TLR agonist activated TAMs, induced their antigen-presenting activity, and thereby transformed the resistant tumors into tumors sensitive to adaptive immune responses such as adoptive transfer of tumor-specific T cell receptor–engineered T cells. These results indicate that the status and function of TAMs have a significant impact on tumor immune sensitivity and that manipulation of TAM functions would be an effective approach for improving the efficacy of immunotherapies.",
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AU - Sawada, Shin Ichi

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AU - Shiku, Hiroshi

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