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.
雑誌名
Journal of Clinical Investigation
巻
129
号
3
ページ
1278 - 1294
発行年
2019-03-01
出版者
American Society for Clinical Investigation
ISSN
00219738
EISSN
15588238
DOI
10.1172/JCI97642
権利
c 2019, American Society for Clinical Investigation.
著者版フラグ
publisher
引用
The Journal of clinical investigation, 129(3), pp.1278-1294; 2019
Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance
JCI129_1278.pdf
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