Format

Send to

Choose Destination
J Clin Invest. 2011 Oct;121(10):4015-29. doi: 10.1172/JCI45862. Epub 2011 Sep 12.

Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.

Author information

1
Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.

Abstract

Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloid-derived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β-expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.

PMID:
21911941
PMCID:
PMC3195459
DOI:
10.1172/JCI45862
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center