Classification of Chemotherapeutic Agents Based on Their DifferentialIn vitroEffects on Dendritic Cells

Abstract

Despite the crucial roles dendritic cells (DC) play in host immunity against cancer, the pharmacologic effects of many chemotherapeutic agents have remained mostly unknown. We recently developed a DC biosensor clone by engineering the stable murine DC line XS106 to express the yellow fluorescent protein (YFP) gene under the control of interleukin (IL)-1B promoter. In this study, the resulting XS106 pIL1-YFP DC clone was used to screen 54 anticancer drugs. Each drug was tested at five concentrations (0.1-10 Mmol/L) for its effects on YFP expression, cell viability, and granulocyte macrophage colonystimulating factor-dependent growth. Our unbiased systematic screening unveiled a striking heterogeneity among the tested anticancer drugs in their effects on the three functional variables. Interestingly, 15 drugs induced significant YFP expression at subcytotoxic concentrations and were thus categorized as ''DC-stimulatory'' anticancer drugs. These drugs were subsequently found to induce at least one of the characteristic maturational changes in mouse bone marrowderived DCs. For example, vinblastine, a prototypic drug of this class, induced the production of IL-1B, IL-6, and IL-12, increased surface expression of CD40, CD80, CD86, and MHC class II, and augmented T cell-stimulatory capacity of DCs. Not only do these results illustrate the differential pharmacologic effects of commonly used chemotherapeutic agents on DCs, they may also provide a conceptual framework for rationale-based selection and combination of anticancer drugs for clinical application.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…An unbiased functional screen of 54 chemotherapeutic agents unveiled striking diversity of the tested drugs on the maturation, survival and growth of DCs. 24 The drugs delivering DC maturation signals at concentrations causing only marginal DC death included topoisomerase inhibitors (for example, etoposide, mitoxantrone, doxorubicin), antimicrotubule agents (for example, vinblastine, paclitaxel, docetaxel) and the two alkylating agents mechlorethamine and diaziquone. 24 In another report, paclitaxel, doxorubicin and methotrexate were shown to promote the ability of murine BM-DCs to present antigens to T-cells in vitro by upregulating antigen-processing machinery gene components, costimulatory molecules and IL-12p70.…”

Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells

“…For the dolastatin 10/vaccination treatment combination, a single dose of dolastatin 10 (0.4 mg/kg) was administered intravenously 15 …”

“…Nevertheless, only a few studies have been reported that have investigated the capacity of antitumor therapeutics to improve DC function. Recent work has identified several cytotoxic agents, including the mitotic spindle inhibitor vinblastine, as potent activators of DC maturation (14)(15)(16). Although the underlying mechanism is still poorly defined, these data clearly highlight a previously unrecognized immunostimulatory activity for vinblastine.…”

TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

“…14 The kinetic experiments showed that there was a time lag between the appearance of the Sytox þ cells (at 6 h) and neutrophil influx (at 16-38 h All these data suggest that the recruitment of neutrophils is associated with apoptotic cells that are killed in situ by doxorubicin. Of note, it has been recently shown that doxorubicin does not have a direct immunostimulatory activity on antigen-presenting cells, 32 thereby excluding a direct effect of doxorubicin on the host cells. Only some apoptotic stimuli, including anthracyclines, induce an immunogenic form of apoptosis characterized by surface exposure of CRT and release of HMGB1.…”