Combined therapy with methotrexate nanoconjugate and dendritic cells with downregulated IL-10R expression modulates the tumor microenvironment and enhances the systemic anti-tumor immune response in MC38 murine colon carcinoma

Szczygieł, Agnieszka; Węgierek-Ciura, Katarzyna; Wróblewska, Anna; Mierzejewska, Jagoda; Rossowska, Joanna; Szermer-Olearnik, Bożena; Świtalska, Marta; Anger‐Góra, Natalia; Goszczyński, Tomasz M.; Pajtasz‐Piasecka, Elżbieta

doi:10.3389/fimmu.2023.1155377

Cited by 6 publications

(9 citation statements)

References 55 publications

(76 reference statements)

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“…However, given that the observed increases in DC abundance intratumorally and from BM-derived DCs are comparable, we are confident that the findings from bmDCs would translate to intratumor DCs. Additionally, bmDCs have previously been used to deduce specific aspects of DC biology using similar culturing conditions to that of this study (109)(110)(111)(112)(113), further supporting the validity of this methodology. Interestingly, through our in vivo and ex vivo studies we observed that L-fuc increases cDC1 and moDC abundance in similar proportions.…”

Section: Discussionsupporting

confidence: 69%

The functional role of L-fucose on dendritic cell function and polarization

Burton,

Bitaraf,

Snyder

et al. 2024

Front. Immunol.

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Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.

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Section: Discussionsupporting

confidence: 69%

The functional role of L-fucose on dendritic cell function and polarization

Burton,

Bitaraf,

Snyder

et al. 2024

Front. Immunol.

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“…DAMPs excreted by dying cells can initiate an immune response, followed by the maturation of the antigen-presenting DCs. However, the immunosuppressive TME hinders the anticancer immune response triggered by DCs ( 43 ). MDSCs, Tregs and tumor cells secrete suppressive cytokines, that can inhibit CTLs ( 44 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Li,

Wang,

Zhang

et al. 2024

Int J Oncol

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The immunogenic cell death (ICD) has aroused great interest in cancer immunotherapy. Doxorubicin (DOX), which can induce ICD, is a widely used chemotherapeutic drug in liver cancer. However, DOX-induced ICD is not potent enough to initiate a satisfactory immune response. Cucurbitacin IIa (CUIIa), a tetracyclic triterpene, is a biologically active compound present in the Cucurbitaceae family. The present study assessed the effects of the combination of DOX and CUIIa on the viability, colony formation, apoptosis and cell cycle of HepG2 cells. In vivo anticancer effect was performed in mice bearing H22 tumor xenografts. The hallmark expression of ICD was tested using immunofluorescence and an ATP assay kit. The immune microenvironment was analyzed using flow cytometry. The combination of CUIIa and DOX displayed potent apoptosis inducing, cell cycle arresting and in vivo anticancer effects, along with attenuated cardiotoxicity in H22 mice. The combination of DOX and CUIIa also facilitated ICD as manifested by elevated high-mobility group box 1, calreticulin and ATP secretion. This combination provoked a stronger immune response in H22 mice, including dendritic cell activation, increment of cytotoxic T cells and T helper 1 cells. Moreover, the proportion of immunosuppressive cells including myeloid-derived suppressor cells, T regulatory cells and M2-polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.

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“…The effect of conjugation of a low-molecular-weight drug with a high-molecularweight carrier provides an optimal hydrodynamic diameter of the obtained HES-MTX nanoconjugate. This enables more efficient accumulation in tumor tissue, mainly through enhanced vascular permeability and retention effect (EPR), which was discussed in more detail in our previous publication (12). Moreover, the anticancer activity of HES-MTX has been confirmed in murine and human leukemia models (10), as well in the murine colon carcinoma MC38 model (12,13).…”

Section: Introductionmentioning

confidence: 88%

“…This enables more efficient accumulation in tumor tissue, mainly through enhanced vascular permeability and retention effect (EPR), which was discussed in more detail in our previous publication ( 12 ). Moreover, the anticancer activity of HES-MTX has been confirmed in murine and human leukemia models ( 10 ), as well in the murine colon carcinoma MC38 model ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 92%

“…HES-MTX nanoconjugate injection in the tail vein (at a dose 20 mg/kg body weight). The HES-MTX preparation was described in detail in our previous papers (10,12). In both experiments, three types of cellular vaccines were usednon-transduced DC/TAg, DC transduced with a control vector (DC/Vctrl/TAg) and DCs modified to overproduce cytokines.…”

Section: Therapeutic Treatment Schedulementioning

confidence: 99%

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Inhibition of MC38 colon cancer growth by multicomponent chemoimmunotherapy with anti-IL-10R antibodies, HES-MTX nanoconjugate, depends on application of IL-12, IL-15 or IL-18 secreting dendritic cell vaccines

et al. 2023

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BackgroundThe tumor microenvironment (TME) provides a conducive environment for the growth and survival of tumors. Negative factors present in TME, such as IL-10, may limit the effectiveness of cellular vaccines based on dendritic cells, therefore, it is important to control its effect. The influence of IL-10 on immune cells can be abolished e.g., by using antibodies against the receptor for this cytokine - anti-IL-10R. Furthermore, the anticancer activity of cellular vaccines can be enhanced by modifying them to produce proinflammatory cytokines, such as IL-12, IL-15 or IL-18. Additionally, an immunomodulatory dose of methotrexate and hydroxyethyl starch (HES-MTX) nanoconjugate may stimulate effector immune cells and eliminate regulatory T cells, which should enhance the antitumor action of immunotherapy based on DC vaccines. The main aim of our study was to determine whether the HES-MTX administered before immunotherapy with anti-IL-10R antibodies would change the effect of vaccines based on dendritic cells overproducing IL-12, IL-15, or IL-18.MethodsThe activity of modified DCs was checked in two therapeutic protocols - immunotherapy with the addition of anti-IL10R antibodies and chemoimmunotherapy with HES-MTX and anti-IL10R antibodies. The inhibition of tumor growth and the effectiveness of the therapy in inducing a specific antitumor response were determined by analyzing lymphoid and myeloid cell populations in tumor nodules, and the activity of restimulated splenocytes.Results and conclusionsUsing the HES-MTX nanoconjugate before immunotherapy based on multiple administrations of anti-IL-10R antibodies and cellular vaccines capable of overproducing proinflammatory cytokines IL-12, IL-15 or IL-18 created optimal conditions for the effective action of these vaccines in murine colon carcinoma MC38 model. The applied chemoimmunotherapy caused the highest inhibition of tumor growth in the group receiving DC/IL-15/IL-15Rα/TAg + DC/IL-18/TAg at the level of 72.4%. The use of cellular vaccines resulted in cytotoxic activity increase in both immuno- or chemoimmunotherapy. However, the greatest potential was observed both in tumor tissue and splenocytes obtained from mice receiving two- or three-component vaccines in the course of combined application. Thus, the designed treatment schedule may be promising in anticancer therapy.

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Combined therapy with methotrexate nanoconjugate and dendritic cells with downregulated IL-10R expression modulates the tumor microenvironment and enhances the systemic anti-tumor immune response in MC38 murine colon carcinoma

Cited by 6 publications

References 55 publications

The functional role of L-fucose on dendritic cell function and polarization

The functional role of L-fucose on dendritic cell function and polarization

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

Inhibition of MC38 colon cancer growth by multicomponent chemoimmunotherapy with anti-IL-10R antibodies, HES-MTX nanoconjugate, depends on application of IL-12, IL-15 or IL-18 secreting dendritic cell vaccines

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