Reprogramming the murine colon cancer microenvironment using lentivectors encoding shRNA against IL-10 as a component of a potent DC-based chemoimmunotherapy.
PBN-AR
Instytucja
Instytut Immunologii i Terapii Doświadczalnej im. Ludwika Hirszfelda Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
angielski
Czasopismo
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (35pkt w roku publikacji)
ISSN
1756-9966
EISSN
Wydawca
BIOMED CENTRAL LTD
DOI
URL
Rok publikacji
2018
Numer zeszytu
1
Strony od-do
126
Numer tomu
37
Identyfikator DOI
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Słowa kluczowe
angielski
Colon carcinoma
Cyclophosphamide
Dendritic cells
IL-10 blocking
Immunotherapy
Interleukin 10
Lentivectors
MC38
Open access
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Creative Commons — Uznanie autorstwa-Na tych samych warunkach
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Język
angielski
Treść
BACKGROUND: The excessive amounts of immunosuppressive factors present in a tumor microenvironment (TME) reduce the effectiveness of cancer vaccines. The main objective of our research was to improve the effectiveness of dendritic cell (DC)-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors encoding shRNA specific to IL-10 (shIL10 LVs) in murine colon carcinoma MC38 model. METHODS: The efficacy of shIL10 LVs in silencing of IL-10 expression was measured both in vitro and in vivo using Real-Time PCR and ELISA assays. In addition, the influence of intratumorally inoculated lentivectors on MC38 tumor microenvironment was examined using flow cytometry method. The effect of applied therapeutic schemes was determined by measurement of tumor growth inhibition and activation state of local and systemic immune response. RESULTS: We observed that intratumorally inoculated shIL10 LVs transduced tumor and TME-infiltrating cells and reduced the secretion of IL-10. Application of shIL10 LVs for three consecutive weeks initiated tumor growth inhibition, whereas treatment with shIL10 LVs and BMDC/TAg did not enhance the antitumor effect. However, when pretreatment with CY was introduced to the proposed scheme, we noticed high MC38 tumor growth inhibition accompanied by reduction of MDSCs and Tregs in TME, as well as activation of potent local and systemic Th1-type antitumor response. CONCLUSIONS: The obtained data shows that remodeling of TME by shIL10 LVs and CY enhances DC activity and supports them during regeneration and actuation of a potent antitumor response. Therefore, therapeutic strategies aimed at local IL-10 elimination using lentiviral vectors should be further investigated in context of combined chemoimmunotherapies.
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Inne
System-identifier
PX-5b4dca99d5deec0772647561
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