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 Qi Wu
A1 Ai-Ling Tian
A1 Bei Li
A1 Marion Leduc
A1 Sabrina Forveille
A1 Peter Hamley
A1 Warren Galloway
A1 Wei Xie
A1 Peng Liu
A1 Liwei Zhao
A1 Shuai Zhang
A1 Pan Hui
A1 Frank Madeo
A1 Yi Tu
A1 Oliver Kepp
A1 Guido Kroemer
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.