Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan;1(1):75-85.
doi: 10.1038/s43018-019-0007-9. Epub 2020 Jan 13.

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

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

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

Daniel Ajona et al. Nat Cancer. 2020 Jan.

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.

PubMed Disclaimer

References

    1. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015). - DOI
    1. Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018). - DOI
    1. Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 15, 457–472 (2015). - DOI
    1. Ward, P. S. & Thompson, C. B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21, 297–308 (2012). - DOI
    1. Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018). - DOI

Publication types

Substances