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The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.

ABSTRACT: It has become evident that the tumor microenvironment plays a pivotal role in the maintenance of cancerous growth. One of the acquired functions of the tumor microenvironment is the suppression of immune responses. Indeed, blocking the inhibitory pathways operational in the microenvironment results in enhanced T-cell-dependent, anti-tumor immunity. Chemotherapeutic drugs not only directly kill tumor cells but also shape the tumor microenvironment and potentiate anti-tumor immunity. Here, we demonstrate that the chemotherapeutic compound oxaliplatin acts as a double-edged sword. Besides killing tumor cells, oxaliplatin bolsters immunosuppressive pathways, resulting in decreased activation of T cells by human plasmacytoid dendritic cells (pDCs). Exposure to oxaliplatin markedly increased expression of the T-cell inhibitory molecule programmed death receptor-ligand 1 (PD-L1) on human pDCs and also TLR9-induced IFN? secretion. Furthermore, oxaliplatin decreased TLR-induced STAT1 and STAT3 expression, and NF-?B-mediated responses. The oxaliplatin induced upregulation of PD-L1 and downregulation of costimulatory molecules CD80 and CD86 resulted in decreased T-cell proliferation. Our results demonstrate that platinum-based anticancer drugs adapt TLR-induced signaling in human pDCs and myeloid DCs (mDCs), thereby downgrading their immunostimulatory potential.

SUBMITTER: Tel J

PROVIDER: S-EPMC3378839 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.

Tel Jurjen J Hato Stanleyson V SV Torensma Ruurd R Buschow Sonja I SI Figdor Carl G CG Lesterhuis W Joost WJ de Vries I Jolanda M IJ

Cancer immunology, immunotherapy : CII 20111223 7

It has become evident that the tumor microenvironment plays a pivotal role in the maintenance of cancerous growth. One of the acquired functions of the tumor microenvironment is the suppression of immune responses. Indeed, blocking the inhibitory pathways operational in the microenvironment results in enhanced T-cell-dependent, anti-tumor immunity. Chemotherapeutic drugs not only directly kill tumor cells but also shape the tumor microenvironment and potentiate anti-tumor immunity. Here, we demo ...[more]

PMID: 22193989

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Project description:Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed.Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant.In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-?-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [(3)H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration-dependently augmented loss of cell viability induced by SN38, while strongly counteracting that induced by oxaliplatin, in both HCT116 and LoVo cells. This reflected neither altered expression of the oxaliplatin transporter Cu(2+)-transporter-1 (CTR1), nor changes in cellular reduced glutathione (GSH), although HCT116 cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction.SLC1A1 expression and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments CRC cell death induced by SN38, while attenuating that induced by oxaliplatin. These findings may point to novel treatment options in treatment-resistant CRC.

Project description:BackgroundChemotherapeutic agents are used to control tumor proliferation. However, their influence in the pre-metastatic niche of target organs has not been well studied. Oxaliplatin (OXA) is a drug applied in standard treatments of colorectal cancer (CRC), while the direct effect of which on the pre-metastatic microenvironment of the liver remains unclear.MethodsModels of liver metastases were established with luciferase expressing CT26 cells in BALB/c and BALB/c-nude mice. Single-cell RNA Sequencing was performed to examine the immune microenvironment in the liver elicited by OXA. Immunofluorescence and flowcytometry were utilized to confirm the changes in the number of immune cells. LDH, CellTrace CFSE Cell Proliferation and apoptosis assays were conducted to explore the impact of OXA on T cells ex vivo. The correlation between chemotherapy-related lymphopenia and metastases was assessed by meta-analysis.ResultsHerein we discovered that administration of OXA prior to the occurrence of liver metastasis actually accelerated tumor development and colonization in the liver. Single-cell RNA sequencing revealed that the landscape of the liver immune microenvironment had been changed to immunosuppressive phenotype. Macrophages after the treatment of OXA exhibited a high ability to inhibit the activation of T cells. Further investigation revealed a significant decrease in the number of T cells in the liver, particularly CD8+ T cells with reduced capacity of proliferation, activation, and killing. When mice were treated with T cell supplementation, the OXA-induced metastasis was notably abolished, indicating that the OXA-primed liver microenvironment could be reversed by the infusion of T cells. Consistent with our findings in mice, a meta-analysis was performed to verify that chemotherapy-related lymphopenia was associated with an inferior prognosis related with high incidence of metastasis, suggesting the pivotal role of chemotherapy in pre-metastatic niche formation. Furthermore, a notable reduction in the count of both macrophages and T cells was observed in the liver of colorectal cancer (CRC) patient undergoing OXA-based chemotherapy.ConclusionsOur findings proposed that immunosuppressive microenvironment in liver induced by OXA enhanced liver metastasis of colorectal cancer, which highlighted a new consideration to balance the pro metastases and anti-cancer possibility of OXA treatment.

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The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.

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The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.

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