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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic / immunology*
  • Granzymes / genetics
  • Granzymes / immunology
  • Humans
  • Immunologic Surveillance*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / pathology
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Primary Cell Culture
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology


  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interferon-gamma
  • Granzymes
  • Gzmb protein, mouse