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PI3K/Akt Signaling Pathway Regulates CD155 Expression Involved in Resistance to Cancer Immunotherapy.

Katsushige Kawase1,2, Shusuke Kawashima1,3, Tatsuya Nishi4,5

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Cancer Immunology Research
|July 31, 2025
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Summary

Resistance to PD-1 blockade therapy is a challenge. This study identifies dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) and PI3K/Akt signaling as key regulators of CD155 expression, offering potential strategies to overcome treatment resistance in cancers.

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Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Anti-programmed death 1 (PD-1)/PD-1 ligand 1 monoclonal antibodies are effective cancer treatments.
  • Resistance to these therapies is a significant clinical problem.
  • The T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 axis is implicated in therapy resistance, but CD155 regulation is not fully understood.

Purpose of the Study:

  • To identify key molecules regulating CD155 expression.
  • To investigate the role of these regulators in modulating CD155 within the tumor microenvironment (TME).
  • To explore therapeutic strategies for overcoming PD-1 blockade resistance.

Main Methods:

  • Clustered regularly interspaced palindromic repeats (CRISPR) screening to identify CD155 regulators.
  • CRISPR/CRISPR-associated protein 9 (Cas9) technology and DYRK1A inhibitors for gene/protein inhibition.
  • Analysis of PI3K/Akt signaling pathway in head and neck squamous cell carcinoma (HNSCC) cell lines and patient samples.

Main Results:

  • Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was identified as a key regulator of CD155 expression.
  • Inhibition of DYRK1A or targeting PI3K/Akt signaling reduced CD155 expression and mitigated PD-1 blockade resistance.
  • In HNSCC patients, CD155 expression correlated with Akt phosphorylation and PD-1 blockade resistance, especially in tumors with high CD8+ T cell infiltration.

Conclusions:

  • The PI3K/Akt signaling pathway plays a crucial role in regulating CD155 expression.
  • Targeting DYRK1A or the PI3K/Akt pathway may overcome PD-1 blockade resistance.
  • These findings are particularly relevant for cancers with an inflamed TME and high CD155 expression.