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Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance
Daisuke Muraoka, … , Naozumi Harada, Hiroshi Shiku
Daisuke Muraoka, … , Naozumi Harada, Hiroshi Shiku
Published January 10, 2019
Citation Information: J Clin Invest. 2019;129(3):1278-1294. https://doi.org/10.1172/JCI97642.
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Research Article Immunology

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

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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.

Authors

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

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Figure 1

Murine fibrosarcoma CMS5a is highly refractory to checkpoint inhibition and lacks a specific CD8+ T cell response.

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Murine fibrosarcoma CMS5a is highly refractory to checkpoint inhibition ...
(A) The murine tumor cell line CT26, CMS7, CMS5a/NY, or CMS5a was subcutaneously inoculated into BALB/c mice. Checkpoint inhibitors including anti–PD-1 (200 μg/mouse), anti–CTLA-4 (100 μg/mouse), and anti-GITR (200 μg/mouse) Abs (n = 8–10 mice per group) or isotype control Abs (n = 8 mice per group) were i.p. injected on days 7, 9, and 11. (B) The experiment was performed in nude mice as described in A. (C and D) Induction of a tumor-specific CD8+ T cell response by checkpoint inhibition was evaluated. BALB/c mice bearing CT26, CMS7, CMS5a/NY, or CMS5a tumors were treated with checkpoint inhibitors. Seven days after the last administration, splenocytes were isolated and restimulated with peptides of predicted neoepitopes or known tumor antigens (AH-1 in CT26 and NY-ESO-1 p81 in CMS5a/NY tumors). The frequency of stimulated CD8+ T cells was quantified by (C) intracellular IFN-γ staining (n = 4 mice per group) or (D) the fold increase in CXCL9 mRNA levels compared with DMSO. The experiments were repeated at least 2 to 4 times with similar results. *P < 0.05, by Mann-Whitney U test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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