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STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis

Chanyu Yue1, Shudan Shen1, Jiehui Deng1

  • 1Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.

Cancer Immunology Research
|May 31, 2015
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) in CD8(+) T cells hinders tumor infiltration by reducing T-cell-derived interferon-gamma (IFNγ). Blocking STAT3 enhances CD8(+) T-cell accumulation and antitumor activity.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Mechanisms

Background:

  • Inefficient CD8(+) T-cell recruitment to tumors is a major hurdle in cancer immunotherapy.
  • Signal transducer and activator of transcription 3 (STAT3) signaling in CD8(+) T cells is known to suppress their antitumor functions and accumulation in tumors, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which STAT3 signaling in CD8(+) T cells inhibits their accumulation within tumors.
  • To identify potential therapeutic targets for enhancing CD8(+) T-cell homing and antitumor efficacy in cancer immunotherapy.

Main Methods:

  • Investigated the role of STAT3 signaling in CD8(+) T cells using cancer models.
  • Analyzed the expression of chemokine (C-X-C motif) ligand 10 (CXCL10) and its receptor CXCR3, as well as interferon-gamma (IFNγ) in T cells and myeloid cells.
  • Utilized genetic ablation of STAT3 in T cells and blocking antibodies against IFNγ and CXCR3.

Main Results:

  • STAT3 signaling in CD8(+) T cells suppresses tumor accumulation by reducing IFNγ expression, which in turn diminishes CXCL10 production by tumor-associated myeloid cells.
  • Ablation of STAT3 in T cells leads to increased expression of the CXCL10 receptor, CXCR3, on CD8(+) T cells, promoting their efficient homing to tumor sites.
  • Blocking IFNγ or CXCR3 abrogated the enhanced accumulation and antitumor effects of STAT3-deficient CD8(+) T cells in tumors.

Conclusions:

  • STAT3 signaling in T cells negatively regulates the IFNγ/CXCR3/CXCL10 axis, crucial for CD8(+) T-cell homing to tumors.
  • Targeting STAT3 in T cells represents a promising strategy to improve CD8(+) T-cell recruitment and enhance the efficacy of cancer immunotherapy and adoptive T-cell therapies.

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