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Inhibitory Immune Checkpoints beyond Programmed Cell Death Ligand 1 in Merkel Cell Carcinoma: Abundant Expression of

Ferdinand Toberer1, Julia K Winkler1, Leroy Atienza Fernandez2

  • 1Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.

Acta Dermato-Venereologica
|July 1, 2025
PubMed

Insights

TIGIT, a molecule regulating T cells, is highly expressed in Merkel cell carcinoma and may drive immune dysfunction. This suggests TIGIT could be a new immunotherapy target for this rare skin cancer.

Area of Science:

  • Oncology
  • Immunology
  • Dermatology

Background:

  • Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer often linked to Merkel cell polyoma virus (MCPyV).
  • Limited therapeutic options exist for advanced MCC after anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy failure.
  • The role of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) in MCC's immunosuppressive microenvironment is largely unknown.

Purpose of the Study:

  • To investigate the expression and potential role of TIGIT in Merkel cell carcinoma.
  • To evaluate the relationship between TIGIT, PD-L1, CD155, CD8, and MCPyV status in MCC.
  • To explore TIGIT as a potential therapeutic target for advanced MCC.

Main Methods:

  • Immunohistochemical analysis of TIGIT, PD-L1, CD155, and CD8 expression in tumor and immune cells from 21 primary MCCs and 6 metastases.
  • Assessment of Tumor Proportion Score (TPS) and Immune Cell Score (ICS) for these markers.
  • RT-PCR to determine MCPyV status.

Main Results:

  • TIGIT was abundantly expressed by tumor and immune cells in MCC, independent of MCPyV status.
  • PD-L1+ immune cells were significantly increased in TIGIT TPS-positive and MCPyV-positive MCC.
  • Intercorrelations were found between PD-L1, TIGIT immune cell expression, and CD8+ infiltrates; PD-L1 IC-positivity correlated with better survival.

Conclusions:

  • TIGIT contributes to local immune dysfunction in Merkel cell carcinoma, beyond PD-L1 and independently of MCPyV.
  • These findings provide a rationale for investigating TIGIT as a novel immunotherapy target in MCC.
  • Further research into TIGIT-based therapies is warranted for advanced Merkel cell carcinoma.

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