Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 3, Pages 1278-1294Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI97642
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Funding
- Japan Society for the Promotion of Science KAKENHI [15K18443, 16H06313]
- Exploratory Research for Advanced Technology of the JST (JST ERATO)
- Grants-in-Aid for Scientific Research [15K18443] Funding Source: KAKEN
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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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