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Tumor microenvironment reprogramming improves nanomedicine-based chemo-immunotherapy in sarcomas.
Charalambous, Antonia; Mpekris, Fotios; Panagi, Myrofora; Voutouri, Chrysovalantis; Michael, Christina; Gabizon, Alberto A; Stylianopoulos, Triantafyllos.
Afiliación
  • Charalambous A; University of Cyprus, Nicosia, Cyprus.
  • Mpekris F; University of Cyprus, Nicosia, Cyprus.
  • Panagi M; University of Cyprus, Nicosia, Cyprus.
  • Voutouri C; University of Cyprus, Nicosia, Cyprus.
  • Michael C; University of Cyprus, Nicosia, Cyprus.
  • Gabizon AA; Hebrew University of Jerusalem, Jerusalem, Israel.
  • Stylianopoulos T; University of Cyprus, Nicosia, Cyprus.
Mol Cancer Ther ; 2024 Jun 28.
Article en En | MEDLINE | ID: mdl-38940284
ABSTRACT
BACKGROUND/

INTRODUCTION:

Sarcomas are a heterogenous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases makes treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which lead to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher, toxic doses of chemotherapy. Here, we tested the mechanotherapeutic ketotifen combined with either pegylated-liposomal doxorubicin (PLD) or pegylated-liposomal co-encapsulated alendronate-doxorubicin (PLAD) plus anti-PD-1 antibody in mouse models of fibrosarcoma and osteosarcoma.

RESULTS:

We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave-elastography (SWE) and contrast-enhanced-ultrasound (CEUS) respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. An additional observation was a trend to improved antitumor response when nano-chemotherapy is given alongside anti-PD1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy, increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper-cell and decreased the number of regulatory-T-cells. In addition, the combination also altered the polarization of tumor associated macrophages, favouring the M1 immune-supportive phenotype over the M2 immuno-suppressive phenotype.

CONCLUSION:

Collectively, our findings provide evidence that ketotifen-induced TME reprograming can improve the efficacy of nanomedicine-based chemoimmunotherapy in sarcomas.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2024 Tipo del documento: Article País de afiliación: Chipre Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2024 Tipo del documento: Article País de afiliación: Chipre Pais de publicación: Estados Unidos