Tumor RNA-transfected dendritic cells and combined therapy with low dose 5-FU induce regression of murine colon cancer

Abstract Background The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. Methods Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. Results Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. Conclusion Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

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Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13133375 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3375

Author(s):

Annabelle Vogt ◽

Farsaneh Sadeghlar ◽

Tiyasha H. Ayub ◽

Carlo Schneider ◽

Christian Möhring ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Dendritic Cells ◽

Tumor Regression ◽

Combined Therapy ◽

Term Survival ◽

Effector Cells ◽

Tumor Environment ◽

The Impact

Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

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Inulin Coated Mn3O4 Nanocuboids Coupled with RNA Interference Reverse Intestinal Tumorigenesis in Apc Knockout Murine Colon Cancer Models

Nanomedicine Nanotechnology Biology and Medicine ◽

10.1016/j.nano.2021.102504 ◽

2021 ◽

pp. 102504

Author(s):

Khushboo Kourani ◽

Poonam Jain ◽

Aviral Kumar ◽

Ashok Kumar Jangid ◽

Guruprasadh Swaminathan ◽

...

Keyword(s):

Colon Cancer ◽

Rna Interference ◽

Intestinal Tumorigenesis ◽

Cancer Models ◽

Murine Colon

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Low-dose Chemotherapeutic Agents Regulate Small Rho GTPase Activity in Dendritic Cells

Journal of Immunotherapy ◽

10.1097/cji.0b013e318176fae4 ◽

2008 ◽

Vol 31 (5) ◽

pp. 491-499 ◽

Cited By ~ 27

Author(s):

Galina V. Shurin ◽

Irina L. Tourkova ◽

Michael R. Shurin

Keyword(s):

Dendritic Cells ◽

Low Dose ◽

Rho Gtpase ◽

Chemotherapeutic Agents ◽

Gtpase Activity

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Low-Dose Lipopolysaccharide Modifies the Production of IL-12 by Dendritic Cells in Response to Various Cytokines

Journal of Clinical and Experimental Hematopathology ◽

10.3960/jslrt.46.31 ◽

2006 ◽

Vol 46 (1) ◽

pp. 31-36 ◽

Cited By ~ 11

Author(s):

Yusuke Saito ◽

Yoshiki Yanagawa ◽

Kazuhiro Kikuchi ◽

Norifumi Iijima ◽

Kazuya Iwabuchi ◽

...

Keyword(s):

Dendritic Cells ◽

Low Dose

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Low-dose versus Standard-Dose Leucovorin in the Treatment of Colon Cancer: Mansoura University Clinical Experience in Facing the Problem of Leucovorin Shortage

Research in Oncology ◽

10.21608/resoncol.2018.6256.1069 ◽

2019 ◽

Vol 0 (0) ◽

pp. 1-5

Author(s):

Hend Elkalla ◽

Mohamed Zahi ◽

Osama Eldamshety

Keyword(s):

Colon Cancer ◽

Clinical Experience ◽

Low Dose ◽

Standard Dose

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Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer

10.21203/rs.3.rs-46781/v1 ◽

2020 ◽

Author(s):

Jing Wu ◽

Hang Cheng ◽

Tete Li ◽

Helei Wang ◽

Guoxia Zang ◽

...

Keyword(s):

Colon Cancer ◽

Dendritic Cells ◽

Rna Sequencing ◽

Immune Cells ◽

Human Colon ◽

Tumour Microenvironment ◽

Plasmacytoid Dendritic Cells ◽

Lymphoid Cells ◽

Human Colon Cancer

Abstract Background: Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain the mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumour types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods: We characterised ILCs and pDCs in the tumour microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results: ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological grade. There was a negative correlation between the numbers of ILC3s and pDCs in tumour tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumour immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumour microenvironment. Conclusions: One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

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