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Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD

Hsin-Fang Tu1, Chun-Jung Ko1,2, Ching-Tai Lee3

  • 1Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Cancer Research
|March 27, 2021
PubMed

Insights

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like afatinib can suppress CD8+ T cell proliferation by targeting CAD. Sequential combination therapy with anti-PD1 immunotherapy shows enhanced efficacy, suggesting optimal timing is crucial for cancer treatment.

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • Combined EGFR-TKI and immune checkpoint blockade (ICB) therapies currently show no added benefit in clinical trials.
  • EGFR-TKIs may potentially attenuate the function of CD8+ T lymphocytes enhanced by ICB.
  • Understanding the interaction between EGFR-TKIs and T cell immunity is critical for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the effect of EGFR-TKI afatinib on CD8+ T lymphocyte function.
  • To identify novel molecular targets of afatinib within T lymphocytes.
  • To determine the optimal timing for combining afatinib with immune checkpoint inhibitors like anti-PD1.

Main Methods:

  • Investigated afatinib's effect on CD8+ T lymphocyte proliferation in vitro and in patients with non-small cell lung cancer.
  • Identified CAD, a key enzyme in de novo pyrimidine biosynthesis, as a novel afatinib target.
  • Evaluated the therapeutic efficacy of sequential versus simultaneous combination therapy of afatinib and anti-PD1 in MC38 and LLC mouse models.

Main Results:

  • Afatinib suppressed CD8+ T lymphocyte proliferation and reduced tumor-infiltrating lymphocytes in mouse models.
  • Early afatinib treatment inhibited T cell proliferation in patients, with unexpected rebound upon long-term exposure, indicating transient effects.
  • Sequential afatinib and anti-PD1 treatment significantly enhanced therapeutic efficacy in mouse models, outperforming simultaneous combination therapy.

Conclusions:

  • Afatinib suppresses CD8+ T lymphocyte proliferation by targeting CAD, revealing a mechanism for its immunomodulatory effects.
  • The transient nature of afatinib's immunosuppression suggests a critical window for combination therapy.
  • Sequential administration of afatinib followed by anti-PD1 immunotherapy offers a promising strategy to overcome current limitations in combined targeted and immune therapy for cancer.

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