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.
The Journal of clinical investigation, 129(3), pp.1278-1294; 2019
Journal
-
- Journal of Clinical Investigation
-
Journal of Clinical Investigation 129 (3), 1278-1294, 2019-03-01
American Society for Clinical Investigation
- Tweet
Keywords
Details 詳細情報について
-
- CRID
- 1050287297240501376
-
- NII Article ID
- 120006987781
-
- ISSN
- 00219738
- 15588238
-
- DOI
- 10.1172/jci97642
-
- HANDLE
- 10069/38899
-
- Text Lang
- en
-
- Article Type
- journal article
-
- Data Source
-
- IRDB
- Crossref
- CiNii Articles
- KAKEN