CE17 - Recherche translationnelle en santé

Induction of CXCR3-associated chemokines and sensitization of "cold" tumors to immunotherapy by screening of novel chemotherapy/targeted therapy combinations – ChemoKin

Submission summary

Since January 2019, Dr. Emeric Limagne has focused his research on chemo-immunotherapy resistance in immunologically "cold" tumors. The present project is a continuation of work done in lung cancer and recently published in Cancer Cell. This work shows that in KRAS mutated cancers, the combination of a MEK inhibitor with chemotherapy triggers the secretion of CXCL10 by cancer cells, the recruitment of CD8+ T cells and restores the efficacy of immunotherapy. This combination promotes optineurin-dependent mitophagy, leading to CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. The overall goal of this new project is to identify combinations that sensitize chemo-immunotherapy resistant tumors in non-small cell lung cancer and triple negative breast cancer in combination with targeted therapy. The idea is to activate in tumor cells the signaling pathways associated with the detection of danger molecules, leading to the expression of CXCL9 and CXCL10. This work will be performed in different preclinical cancer models genetically modified to be more representative of human cancers resistant to chemo-immunotherapy. These models will be derived from the LLC1 and 4T1 cell lines. A library of targeted therapies will be used to identify the best CXCL9 and CXCL10 inducers in combination with chemotherapy. In vivo, the induction of the immune response by our candidate combinations as well as the potential synergy in association with immunotherapy will be studied. Finally, the exploration of the molecular mechanism(s) will be performed both in mice using CRISPR/Cas9 technology and in humans on retrospective cohorts of patients treated with neo-adjuvant chemotherapy. As with the chemotherapy/MEKi combination, we hope that this project will allow us to identify molecular alterations associated with the failure of chemotherapy to recruit CD8+ T cells and to circumvent this problem with targeted therapies. Taken as a whole, this project should help optimize chemo-immunotherapy regimens in "cold" tumors.

Project coordinator

Monsieur Emeric LIMAGNE (Centre Georges-François Leclerc)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRC Centre Georges-François Leclerc

Help of the ANR 364,249 euros
Beginning and duration of the scientific project: October 2022 - 48 Months

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