Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Shevchenko, Ivan; Karakhanova, Svetlana; Soltek, Sabine; Link, Julia; Bayry, Jagadeesh; Werner, Jens; Umansky, Viktor; Bazhin, Alexandr V.

doi:10.1002/ijc.27990

Cited by 152 publications

(129 citation statements)

References 54 publications

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“…Also other chemotherapeutic compounds may affect Tregs and immune suppressive myeloid cells. Gemcitabine is known to reduce both Tregs and MDSCs in mice and in patients with ovarian cancer [53,54,80,100,101]. A selective decrease in MDSCs was also observed after treatment with 5-fluorouracil (5-FU) [102].…”

Section: Administration Of Chemotherapy Before Vaccination Alleviatesmentioning

confidence: 99%

The importance of correctly timing cancer immunotherapy

Nejad

Welters

Arens

et al. 2016

Expert Opinion on Biological Therapy

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Introduction:The treatment options for cancer-surgery, radiotherapy and chemotherapy-are now supplemented with immunotherapy. Previously underappreciated but now gaining strong interest are the immune modulatory properties of the three conventional modalities. Moreover, there is a better understanding of the needs and potential of the different immune therapeutic platforms. Key to improved treatment will be the combinations of modalities that complete each other's shortcomings. Area covered: Tumor-specific T-cells are required for optimal immunotherapy. In this review, the authors focus on the correct timing of different types of chemotherapeutic agents or immune modulators and immunotherapeutic drugs, not only for the activation and expansion of tumor-specific Tcells but also to support and enhance their anti-tumor efficacy. Expert opinion: At an early phase of disease, clinical success can be obtained using single treatment modalities but at later disease stages, combinations of several modalities are required. The gain in success is determined by a thorough understanding of the direct and indirect immune effects of the modalities used. Profound knowledge of these effects requires optimal tuning of immunomonitoring. This will guide the appropriate combination of treatments and allow for correct sequencing the order and interval of the different therapeutic modalities. ARTICLE HISTORY

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Section: Administration Of Chemotherapy Before Vaccination Alleviatesmentioning

confidence: 99%

The importance of correctly timing cancer immunotherapy

Nejad

Welters

Arens

et al. 2016

Expert Opinion on Biological Therapy

View full text Add to dashboard Cite

show abstract

“…The combination therapy also led to a decrease in the percentage of splenic MDCSs compared to immunotherapy (12. 16.66 § 2.71%, p < 0.05). In contrast, splenic Tregs were decreased in mice treated with the combined regimen (13.33 § 3.9%) compared to immunotherapy alone or the control treatment.…”

Section: E1095433-4mentioning

confidence: 87%

“…[16][17][18][19] In addition to its direct cytolytic activity on tumor cells, Gem was shown to induce the enhancement of T-cellmediated antitumor effects in pre-clinical studies. 20 Previously, we observed that the administration of recombinant lipoprotein-based vaccination as a monotherapy was not sufficient for therapeutic success in mice bearing advanced-stage tumors (3 1 cm diameter).…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy

Chang

Yeh

et al. 2015

OncoImmunology

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Although immunotherapy is an attractive approach for cancer treatment, increasing evidence has shown that the combination of immunotherapy with other treatment modalities may improve the outcome of advanced malignancy. We combined the anticancer drug gemcitabine (Gem) with recombinant lipoprotein-based immunotherapy (rlipo-E7m/CpG) to treat advanced cancer. Mice bearing huge solid tumors (3 12 mm in diameter) or orthotopic cervical cancer were treated with a therapeutic regimen consisting of rlipo-E7m/CpG and Gem. In addition, tumor-infiltrating immune cells were quantified by flow cytometry following the chemotherapy and/or immunotherapy. We observed the eradication of huge tumors following the administration of Gem on days 21, 24, and 27 or following rlipo-E7m/CpG therapy on day 30 post-tumor implantation. The combination therapy substantially reduced the number of immunosuppressive cells (CD11b C T cells compared to Gem or rlipo-E7m/CpG monotherapy. Interestingly, the administration of Gem and rlipo-E7m/CpG reduced the quantity of programmed cell death protein 1 (PD-1)-expressing antigen-specific cytotoxic T lymphocytes (CTLs) in the regressing tumors. These findings demonstrated that Gem enhances the eradication of huge tumors by inhibiting a broad range of immunosuppressive cells when combined with immunotherapy. Based on the promising results from this animal study, Gem chemotherapy combined with recombinant lipoimmunogen-based immunotherapy represents a feasible approach for cancer therapy.

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“…Immune tolerance is referred as the immunosuppressive capabilities of tumor-induced inhibitory cells which are mainly comprised of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) [9]. Cyclophosphamide or gemcitabine with low dose treatment can selectively deplete Treg in patients with cancer or in tumor bearing mice [10]- [12]; Paclitaxel with noncytotoxic dose can inhibit MDSC and restore the anti-tumor activity of CD8 + T cells [13]; and 5-FU shows a pronounced effect on MDSC depletion [4]. Overall, approaches to deplete endogenous suppressive cell populations can improve the efficiency of anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Proliferative Effect of 5-Fluorouracil on Tumor Is Highly Associated with the Renewal of Peripheral White Blood Cells

Qian¹,

Qian²,

Chen³

et al. 2015

JCT

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The efficacy of chemotherapy is thought to be direct killing of tumor cells, but documented studies have been shown that immunity plays a role in its effectiveness. In a pilot study to observe the bone marrow suppression and regeneration in tumor bearing mice induced by single dose injection of 5-fluorouracil (5-FU), we unexpectedly found that tumors grew fast as bone marrow mononuclear cells (BMC) and peripheral white blood cells (PWBC) were decreased quickly during myelosuppression meanwhile significantly slow as repopulating of BMC and PWBC during bone marrow regeneration after 5-FU treatment, no matter whether in low or high dose administration, but the higher the dose was, the lower of the nadir of BMC and PWBC were reached to, as well as the much more powerful duration and strength of the repopulated BMC and PWBC, suggested that the immunity might be a predominant drive in 5-FU chemotherapy. Due to the fact that BMC is the source of PWBC which is its final maturational and functional form, it could be proposed that the anti-proliferative effect of 5-FU on tumor is highly associated with the renewal of PWBC.

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Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Cited by 152 publications

References 54 publications

The importance of correctly timing cancer immunotherapy

The importance of correctly timing cancer immunotherapy

Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy

The Anti-Proliferative Effect of 5-Fluorouracil on Tumor Is Highly Associated with the Renewal of Peripheral White Blood Cells

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