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- Title
Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells.
- Authors
Hosoi, Akihiro; Matsushita, Hirokazu; Shimizu, Kanako; Fujii, Shin‐ichiro; Ueha, Satoshi; Abe, Jun; Kurachi, Makoto; Maekawa, Ryuji; Matsushima, Kouji; Kakimi, Kazuhiro
- Abstract
Complex interactions among multiple cell types contribute to the immunosuppressive milieu of the tumor microenvironment. Using a murine model of adoptive T-cell immunotherapy (ACT) for B16 melanoma, we investigated the impact of tumor infiltrating cells on this complex regulatory network in the tumor. Transgenic pmel-1-specific cytotoxic T lymphocytes (CTLs) were injected intravenously into tumor-bearing mice and could be detected in the tumor as early as on day 1, peaking on day 3. They produced IFN-γ, exerted anti-tumor activity and inhibited tumor growth. However, CTL infiltration into the tumor was accompanied by the accumulation of large numbers of cells, the majority of which were CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs). Notably, CD11b+Gr1intLy6G−Ly6C+ monocytic MDSCs outnumbered the CTLs by day 5. They produced nitric oxide, arginase I and reactive oxygen species, and inhibited the proliferation of antigen-specific CD8+ T cells. The anti-tumor activity of the adoptively-transferred CTLs and the accumulation of MDSCs both depended on IFN-γ production on recognition of tumor antigens by the former. In CCR2−/− mice, monocytic MDSCs did not accumulate in the tumor, and inhibition of tumor growth by ACT was improved. Thus, ACT triggered counter-regulatory immunosuppressive mechanism via recruitment of MDSCs. Our results suggest that strategies to regulate the treatment-induced recruitment of these MDSCs would improve the efficacy of immunotherapy.
- Publication
International Journal of Cancer, 2014, Vol 134, Issue 8, p1810
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.28506