Local anesthetics elicit immune-dependent anticancer effects - UNICANCER
Article Dans Une Revue JOURNAL FOR IMMUNOTHERAPY OF CANCER Année : 2022

Local anesthetics elicit immune-dependent anticancer effects

Alejandra Wu Chuang
  • Fonction : Auteur
Wei Xie
  • Fonction : Auteur
Shuai Zhang
  • Fonction : Auteur
Peter Van Endert
  • Fonction : Auteur

Résumé

Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice. Results In vitro, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2 alpha and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2 alpha phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. In vivo, locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics. Conclusion Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
Fichier principal
Vignette du fichier
e004151.full.pdf (7.95 Mo) Télécharger le fichier
Origine Publication financée par une institution
licence

Dates et versions

hal-04085321 , version 1 (19-09-2024)

Licence

Identifiants

Citer

Lucillia Bezu, Alejandra Wu Chuang, Allan Sauvat, Juliette Humeau, Wei Xie, et al.. Local anesthetics elicit immune-dependent anticancer effects. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2022, 10 (4), ⟨10.1136/jitc-2021-004151⟩. ⟨hal-04085321⟩
28 Consultations
0 Téléchargements

Altmetric

Partager

More