Publicaciones científicas
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
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.
CITA DEL ARTÍCULO Nat Cancer. 2020 Jan;1(1):75-85. doi: 10.1038/s43018-019-0007-9. Epub 2020 Jan 13.
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