Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 9, Issue 6, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-002722
Keywords
immunotherapy; breast neoplasms; systems biology
Categories
Funding
- Chinese scholarship council
- Ile de France DIM ELICIT initiative
- Natural Science Foundation of Hubei grant [2020CFA026]
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)-Projets blancs
- AMMICa US23/CNRS UMS3655
- Association pour la recherche sur le cancer (ARC)
- Association 'Ruban Rose'
- Canceropole Ile-de-France
- Fondation pour la Recherche Medicale (FRM)
- European Union
- High-end Foreign Expert Program in China [GDW20171100085]
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LabEx Immuno-Oncology [ANR-18-IDEX-0001]
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- IdEx Universite de Paris [ANR-18-IDEX-0001]
- Austrian Science Fund FWF [SFB LIPOTOX F3007, F3012, W1226, P29203, P29262, P27893, P31727]
- Austrian Federal Ministry of Education, Science and Research
- University of Graz [BMWFW-80.109/0001-WF/V/3b/2015]
- field of excellence BioHealth
- BioTechMed-Graz flagship project EPIAge
- NAWI Graz
- Equipex Onco--Pheno--Screen
- European Joint ProgrammeProgram on Rare Diseases (EJPRD)
- Gustave Roussy Odyssea
- Fondation Carrefour
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The study identified PPP as a potent autophagy inducer by inhibiting the tyrosine kinase activity of IGF1R. In animal models, PPP improved the therapeutic efficacy of chemoimmunotherapy, but this effect was lost when tumors were insensitive to PPP or autophagy-incompetent.
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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