Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance
Daisuke Muraoka, … , Naozumi Harada, Hiroshi Shiku
Daisuke Muraoka, … , Naozumi Harada, Hiroshi Shiku
Published March 1, 2019; First 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

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 7

Induction of antigen presentation by TAMs enhances the accumulation of specific CD8+ T cells at the local tumor site.

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Induction of antigen presentation by TAMs enhances the accumulation of s...
(A) The complex of CHP with 9m epitope–containing LPA (50 μg) was intravenously injected with CpG ODN (50 μg) into CMS5a tumor–bearing BALB/c mice (n = 2 mice per group) on day 7. Naive CD8+ cells isolated from DUC18/CD90.1 mice were infused into the same mice on day 8. The tumors were removed from the mice on day 11, and the frequency of CD90.1+CD8+ T cells in the tumors was determined by flow cytometry. Data from 3 experiments were pooled and represent the mean ± SD. (B and C) CMS5a tumor–bearing BALB/c mice (n = 3–4 per group) were treated as in A, and the tumors were isolated on day 11. The concentration of chemokines and cytokines in the tumors was measured by Bio-Plex assay. Circles in the graph indicate the values of the individual tumors, and bars show the mean. *P < 0.05, by 2-factor factorial ANOVA followed by Tukey-Kramer post hoc analysis. (D) Expression of immune checkpoint molecules on CD90.1+CD8+ T cells infiltrating the tumors isolated on day 11 was analyzed by flow cytometry (n = 3–4 per group). Data represent the mean ± SD. *P < 0.05, by 2-factor factorial ANOVA followed by Tukey-Kramer post hoc analysis. The experiments were repeated at least 2 to 3 times with similar results.