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Inflammation drives nitric oxide synthase 2 expression by γδ T cells and affects the balance between melanoma and

Laetitia Douguet1,2,3, Lloyd Bod1,2,3, Laura Labarthe1,2,3

  • 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France.

Oncoimmunology
|September 20, 2018
PubMed

Insights

Interleukin-1β and Interleukin-6 drive inducible nitric oxide synthase (NOS2) expression in γδ T cells, promoting melanoma growth. Neutralizing these cytokines reduced tumor progression and induced vitiligo in mice.

Area of Science:

  • Immunology
  • Oncology
  • Dermatology

Background:

  • Inducible nitric oxide synthase (NOS2) expression by myeloid-derived suppressor cells (MDSCs) is crucial for cancer immune evasion.
  • γδ T cells in melanoma also express NOS2, promoting a pro-tumor phenotype.
  • Mechanisms regulating NOS2 in tumor-induced γδ T cells are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms controlling NOS2 expression in γδ T cells within the tumor microenvironment.
  • To explore the role of inflammatory cytokines in regulating γδ T cell function and melanoma progression.
  • To examine the link between melanoma, γδ T cells, NOS2, and vitiligo development.

Main Methods:

  • Utilized a transgenic mouse model (Ret mice) developing spontaneous metastatic melanoma.
  • Administered in vivo neutralization of interleukin (IL)-1β and IL-6.
  • Assessed NOS2 and IL-17 production by γδ T cells.
  • Monitored tumor cell dissemination and vitiligo development.

Main Results:

  • IL-1β and IL-6 were identified as key drivers of NOS2 expression in γδ T cells.
  • Neutralization of IL-1β and IL-6 reduced NOS2 and IL-17 production by γδ T cells.
  • Cytokine neutralization delayed tumor dissemination and induced vitiligo in a subset of mice.
  • Mice with less aggressive melanoma and vitiligo showed lower inflammatory cytokine levels and reduced tumor-infiltrating γδ T cells expressing NOS2.

Conclusions:

  • Inflammation levels at the tumor site dictate NOS2 expression in γδ T cells.
  • Targeting IL-1β and IL-6 may offer a therapeutic strategy for melanoma by modulating γδ T cell function.
  • The study highlights a connection between melanoma, γδ T cell-driven inflammation, and the development of associated vitiligo.
Keywords:
NOS2interleukin 1βinterleukin 6melanomapro-tumorogenic γδ T cells

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