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 4

TAM activation in sensitive tumors is dependent on IFN-γ signaling and T cells.

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TAM activation in sensitive tumors is dependent on IFN-γ signaling and T...
(A) CMS5a/NY or CMS5a cells were subcutaneously inoculated into WT BALB/c mice (gray, n = 3), BALB/c IFN-γ–/– mice (blue, n = 3), or BALB/cnu/nu mice (red, n = 3). Seven days after inoculation, TAMs were isolated and analyzed for PD-L1 and MHC class II expression. Histograms show representative data. (B) The experiment was performed as described in A, but in CD8+ T cell–depleted (red, n = 3), CD4+ T cell–depleted (blue, n = 3), or CD8+ T cell– and CD4+ T cell–depleted (green, n = 3) mice. (C) TAMs were sorted from CMS5a/NY tumors grown in WT BALB/c mice (n = 3), BALB/c IFN-γ–/– mice (n = 3), or BALB/cnu/nu mice (n = 3) and were cocultured for 72 hours as antigen-presenting cells (1 × 105, 0.25 × 105, or 0.125 × 105 cells/well, respectively) with DUC18 CD8+ T cells as responder cells. Antigen-dependent proliferation of DUC18 CD8+ T cells was measured using a CFSE dilution assay. Histograms show representative data, and the numbers shown in the histograms indicate the percentage of proliferating CD8+ T cells. 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 4 times with similar results.