Abstract
Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy.
Highlights
Cancer vaccines hold great promise for cancer therapy due to their highly specific, well tolerated, and long-lasting anti-tumor effect
Our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through major histocompatibility complex class I (MHC I), which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo-/immuno-therapy
Our results demonstrate that the topoisomerase I-targeting anticancer drug topotecan (TPT) induces elevated secretion of multiple cytokines and increased MHC I expression in breast cancer cells
Summary
Cancer vaccines hold great promise for cancer therapy due to their highly specific, well tolerated, and long-lasting anti-tumor effect. Pretreatment with low-dose cyclophosphamide (CTX), as a single agent or in combination with other anticancer drugs, has been shown to enhance cytotoxic T lymphocyte (CTL)-mediated antitumor immune response to tumor vaccination in animal models [4,5]. In metastatic pancreatic cancer patients receiving a cell-based cancer vaccine, low-dose CTX administration has been shown to enhance antigen-specific CTL cytotoxicity [6]. It appears that chemotherapy could restore immune surveillance perhaps by breaking the tumor immune escape mechanisms. Low-dose chemotherapeutics have been observed to selectively deplete T regulatory cells that are known to represent a major tumor immune escape mechanism [7,8,9,10]
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