Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade
Menée à l'aide de modèles murins de cancer du poumon et à l'aide d'échantillons plasmatiques prélevés sur 40 patients atteints d'un cancer du poumon à petites cellules traité par anti-PD-1–PD-L1, cette étude met en évidence un mécanisme par lequel une privation alimentaire de courte durée réduit les niveaux plasmatiques du facteur IGF-1 et sensibilise les cellules cancéreuses aux inhibiteurs du point de contrôle immunitaire PD-1
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.