2. Academic Validation
  3. Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD

Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD

  • Cancer Res. 2021 Jun 15;81(12):3270-3282. doi: 10.1158/0008-5472.CAN-20-3436.
Hsin-Fang Tu 1,  Chun-Jung Ko 1 2,  Ching-Tai Lee 3,  Cheng-Fan Lee 1,  Shao-Wei Lan 1,  Hsin-Hsien Lin 1,  Hsin-Ying Lin 1,  Chia-Chi Ku 4,  Der-Yen Lee 5,  I-Chun Chen 1,  Ya-Hui Chuang 6,  Francisco Del Caño-Ochoa 7 8,  Santiago Ramón-Maiques 7 8,  Chao-Chi Ho 9,  Ming-Shyue Lee 10,  Geen-Dong Chang 11
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2 Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 4 Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 5 Graduate Institute of Integrated Medicine/Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
  • 6 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 7 Instituto de Biomedicina de Valencia (IBV-CSIC), Valencia, Spain.
  • 8 Group 739, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-Instituto de Salud Carlos III, Valencia, Spain.
  • 9 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. mslee2006@ntu.edu.tw ccho1203@ntu.edu.tw.
  • 10 Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. mslee2006@ntu.edu.tw ccho1203@ntu.edu.tw.
  • 11 Graduate Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
PMID: 33771897 DOI: 10.1158/0008-5472.CAN-20-3436
Abstract

Current clinical trials of combined EGFR-tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8+ T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8+ T lymphocyte proliferation, and we identify CAD, a key Enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)-bearing mice. Early afatinib treatment inhibited CD8+ T lymphocyte proliferation in patients with non-small cell lung Cancer, but their proliferation unexpectedly rebounded following long-term treatment. This suggests a transient immunomodulatory effect of afatinib on CD8+ T lymphocytes. Sequential treatment of afatinib with anti-PD1 immunotherapy substantially enhanced therapeutic efficacy in MC38 and LLC-bearing mice, while simultaneous combination therapy showed only marginal improvement over each single treatment. These results suggest that afatinib can suppress CD8+ T lymphocyte proliferation by targeting CAD, proposing a timing window for combined therapy that may prevent the dampening of ICB efficacy by EGFR-TKIs. SIGNIFICANCE: This study elucidates a mechanism of afatinib-mediated immunosuppression and provides new insights into treatment timing for combined targeted therapy and immunotherapy. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3270/F1.large.jpg.

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