Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models

Myrofora Panagi, Fotios Mpekris, Pengwen Chen, Chrysovalantis Voutouri, Yasuhiro Nakagawa, John D. Martin, Tetsuro Hiroi, Hiroko Hashimoto, Philippos Demetriou, Chryso Pierides, Rekha Samuel, Andreas Stylianou, Christina Michael, Shigeto Fukushima, Paraskevi Georgiou, Panagiotis Papageorgis, Petri Ch. Papaphilippou, Laura Koumas, Paul Costeas, Genichiro Ishii, Motohiro Kojima, Kazunori Kataoka, Horacio Cabral () and Triantafyllos Stylianopoulos ()
Additional contact information
Myrofora Panagi: University of Cyprus
Fotios Mpekris: University of Cyprus
Pengwen Chen: The University of Tokyo
Chrysovalantis Voutouri: University of Cyprus
Yasuhiro Nakagawa: The University of Tokyo
John D. Martin: The University of Tokyo
Tetsuro Hiroi: National Cancer Center, Kashiwanoha
Hiroko Hashimoto: National Cancer Center, Kashiwanoha
Philippos Demetriou: The Center for the Study of Hematological and other Malignancies
Chryso Pierides: The Center for the Study of Hematological and other Malignancies
Rekha Samuel: Christian Medical College Campus Bagayam
Andreas Stylianou: University of Cyprus
Christina Michael: University of Cyprus
Shigeto Fukushima: The University of Tokyo
Paraskevi Georgiou: European University of Cyprus
Panagiotis Papageorgis: European University of Cyprus
Petri Ch. Papaphilippou: University of Cyprus
Laura Koumas: The Center for the Study of Hematological and other Malignancies
Paul Costeas: The Center for the Study of Hematological and other Malignancies
Genichiro Ishii: National Cancer Center, Kashiwanoha
Motohiro Kojima: National Cancer Center, Kashiwanoha
Kazunori Kataoka: Kawasaki Institute of Industrial Promotion
Horacio Cabral: The University of Tokyo
Triantafyllos Stylianopoulos: University of Cyprus

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.

Date: 2022
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DOI: 10.1038/s41467-022-34744-1

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