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 6

Induction of antigen presentation by TAMs improves tumor immune sensitivity.

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Induction of antigen presentation by TAMs improves tumor immune sensitiv...
CMS5a cells were subcutaneously inoculated into BALB/c mice. 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 on days 7 and 11. (A) Checkpoint inhibitors including anti–PD-1 (200 μg/mouse), anti–CTLA-4 (100 μg/mouse), and anti-GITR (200 μg/mouse) Abs or isotype Abs were intraperitoneally injected on days 7, 9, and 11, or (B–F) naive CD8+ cells isolated from DUC18 mice were infused on days 8 and 12 into the same mice. Tumor size was then monitored. (D) CLs (200 μl) were intravenously injected into CMS5a tumor–bearing mice on days 4 and 8, and other reagents were administered as in B. (E) CMS5a tumors were inoculated into BALB/c mice on day 0. Control or 9m peptide–pulsed bone marrow–derived macrophages were directly injected into the CMS5a tumor on days 6 and 10. DUC18 CD8+ cells were infused on days 7 and 11 (n = 8–10 mice per group). *P < 0.05, by Steel-Dwass test. Experiments in A–E were performed at least 2 to 3 times with similar results. (F) Rhodamine-labeled CHP:LPA complex and CpG ODN were intravenously injected into CMS5a tumor–bearing BALB/c mice on day 7, followed by infusion of DUC18/CD90.1 mouse-derived CD8+ cells on day 8. Cryosections of the treated tumor were prepared and stained with anti-CD90.1 mAb (green). TAMs engulfing the labeled CHP:LPA complex are shown in red; blue indicates F4/80+ TAMs. Colocalization of CHP:LPA-ingested TAMs and specific CD8+ T cells is indicated by arrows. Scale bars: 50 μm. The experiments were repeated 2 times with similar results.