Tumor immune escape by the loss of homeostatic chemokine expression

Area of Science:

• Immunology
• Dermatology
• Oncology

Background:

• CCL27 is a keratinocyte-specific chemokine crucial for skin immune responses.
• T cell homing to the skin is regulated by CCL27.
• Skin tumors may exploit immune evasion mechanisms.

Purpose of the Study:

• To investigate the role of CCL27 in skin tumor immune evasion.
• To elucidate the signaling pathways involved in CCL27 down-regulation in skin cancers.
• To determine the impact of CCL27 on anti-tumor immunity in vivo.

Main Methods:

• Quantitative analysis of CCL27 mRNA and protein expression in healthy skin and skin tumors.
• Assessment of phosphorylated ERK levels as an indicator of EGFR-Ras signaling activation.
• In vitro experiments using keratinocytes stimulated with EGF or Ras oncogene, and treated with an EGFR tyrosine kinase inhibitor.
• In vivo studies in mice involving CCL27 neutralization and tumor growth assessment.

Main Results:

• CCL27 expression was progressively lost in actinic keratoses, basal cell carcinomas, and squamous cell carcinomas compared to healthy skin.
• Elevated phosphorylated ERK levels indicated activated EGFR-Ras signaling in skin lesions and tumors.
• EGFR-Ras pathway activation suppressed CCL27 production in keratinocytes, while inhibition increased it.
• CCL27 neutralization in mice led to reduced leukocyte infiltration and enhanced primary tumor growth.

Conclusions:

• Skin tumors down-regulate CCL27 expression via EGFR-Ras-MAPK pathway activation to evade T cell-mediated immunity.
• Loss of CCL27 impairs anti-tumor immune responses and promotes tumor progression.
• This study reveals a novel immune evasion mechanism utilized by keratinocyte-derived skin tumors.