IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms− - Faculté des Sciences de Sorbonne Université Accéder directement au contenu
Article Dans Une Revue Journal for Immunotherapy of Cancer Année : 2021

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms−

Bei Li
  • Fonction : Auteur
Peter Hamley
  • Fonction : Auteur
Warren Galloway
  • Fonction : Auteur
Yi Tu
  • Fonction : Auteur

Résumé

Background Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers. Results Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis. Conclusion Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
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Dates et versions

hal-03263461 , version 1 (17-06-2021)

Identifiants

Citer

Qi Wu, Ai-Ling Tian, Bei Li, Marion Leduc, Sabrina Forveille, et al.. IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms−. Journal for Immunotherapy of Cancer, 2021, 9 (6), pp.e002722. ⟨10.1136/jitc-2021-002722⟩. ⟨hal-03263461⟩
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