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Eur J Immunol. 2015 Jan;45(1):71-81. doi: 10.1002/eji.201444467. Epub 2014 Nov 10.

CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation.

Author information

1
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
2
Department of Molecular Medicine, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
3
Department of Medical Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
4
Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
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Contributed equally

Abstract

Increasing evidence suggests that premetastatic niches, consisting mainly of myeloid cells, provide microenvironment critical for cancer cell recruitment and survival to facilitate metastasis. While CD8(+) T cells exert immunosurveillance in primary human tumors, whether they can exert similar effects on myeloid cells in the premetastatic environment is unknown. Here, we show that CD8(+) T cells are capable of constraining premetastatic myeloid cell accumulation by inducing myeloid cell apoptosis in C57BL/6 mice. Ag-specific CD8(+) T-cell cytotoxicity against myeloid cells in premetastatic lymph nodes is compromised by Stat3. We demonstrate here that Stat3 ablation in myeloid cells leads to CD8(+) T-cell activation and increased levels of IFN-γ and granzyme B in the premetastatic environment. Furthermore, Stat3 negatively regulates soluble Ag cross-presentation by myeloid cells to CD8(+) T cells in the premetastatic niche. Importantly, in tumor-free lymph nodes of melanoma patients, infiltration of activated CD8(+) T cells inversely correlates with STAT3 activity, which is associated with a decrease in number of myeloid cells. Our study suggested a novel role for CD8(+) T cells in constraining myeloid cell activity through direct killing in the premetastatic environment, and the therapeutic potential by targeting Stat3 in myeloid cells to improve CD8(+) T-cell immunosurveillance against metastasis.

KEYWORDS:

CTLs; Immunosurveillance; Premetastatic myeloid cell accumulation; Stat3

PMID:
25310972
PMCID:
PMC4293284
DOI:
10.1002/eji.201444467
[Indexed for MEDLINE]
Free PMC Article

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