RT Journal Article
SR Electronic
T1 IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002722
DO 10.1136/jitc-2021-002722
VO 9
IS 6
A1 Wu, Qi
A1 Tian, Ai-Ling
A1 Li, Bei
A1 Leduc, Marion
A1 Forveille, Sabrina
A1 Hamley, Peter
A1 Galloway, Warren
A1 Xie, Wei
A1 Liu, Peng
A1 Zhao, Liwei
A1 Zhang, Shuai
A1 Hui, Pan
A1 Madeo, Frank
A1 Tu, Yi
A1 Kepp, Oliver
A1 Kroemer, Guido
YR 2021
UL http://jitc.bmj.com/content/9/6/e002722.abstract
AB 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.Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. All data supporting the findings of this study are available within the article and its online supplemental information files and from the corresponding author on reasonable request.