Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

  • Nat Cancer. 2020 Jan;1(1):75-85. doi: 10.1038/s43018-019-0007-9.
Daniel Ajona  1  2  3  4 ,  Sergio Ortiz-Espinosa  5  6 ,  Teresa Lozano  7  8 ,  Francisco Exposito  5  7  9  10 ,  Alfonso Calvo  5  7  9  10 ,  Karmele Valencia  5  7  9  6 ,  Miriam Redrado  5  7 ,  Ana Remírez  5 ,  Fernando Lecanda  5  7  9  10 ,  Diego Alignani  7  9  11 ,  Juan J Lasarte  7  8 ,  Irati Macaya  5  7 ,  Yaiza Senent  5 ,  Cristina Bértolo  5  7  9 ,  Cristina Sainz  5  7  9 ,  Ignacio Gil-Bazo  5  7  9  12 ,  Iñaki Eguren-Santamaría  12 ,  Jose M Lopez-Picazo  7  9  12 ,  Alvaro Gonzalez  7  6  13 ,  Jose L Perez-Gracia  7  9  12 ,  Carlos E de Andrea  7  9  10  14 ,  Silvestre Vicent  5  7  9 ,  Miguel F Sanmamed  7  9  8  12 ,  Luis M Montuenga  5  7  9  10 ,  Ruben Pio  5  7  9  6
Affiliations
  • 1. Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. [email protected].
  • 2. Navarra Institute for Health Research (IdISNA), Pamplona, Spain. [email protected].
  • 3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [email protected].
  • 4. Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain. [email protected].
  • 5. Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 6. Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
  • 7. Navarra Institute for Health Research (IdISNA), Pamplona, Spain.
  • 8. Program in Immunology and Immunotherapy, CIMA, University of Navarra, Pamplona, Spain.
  • 9. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 10. Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
  • 11. Cytometry Platform, CIMA, University of Navarra, Pamplona, Spain.
  • 12. Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 13. Clinical Chemistry Department, Clínica Universidad de Navarra, Pamplona, Spain.
  • 14. Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
PMID: 35121837 DOI: 10.1038/s43018-019-0007-9
Abstract

Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell Lung Cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit Lung Cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell Lung Cancer, high plasma levels of IGF-1 or high IGF-1R expression in Tumors was associated with resistance to anti-PD-1-programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.

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