Chemotherapeutics and Radiation Stimulate MHC Class I Expression through Elevated Interferon-beta Signaling in Breast Cancer Cells

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.

Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence

“…While the observed results cannot be fully attributed to CDDP’s actions alone, they nevertheless highlight the important immunological impact such real-world, CDDP-based regimens may have. Still, a single, relatively low dose of CDDP has been demonstrated to elevate the expression of total cellular MHC class I in breast cancer ZR-75-1 cells (10); MHC class I expression was likewise increased with exposure of HPV-16 E7-expressing TC-1 murine tumor cells to CDDP in vitro (11). …”

Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer

“…However, recent reports have shown that several chemotherapeutic drugs altered the local immune state, affecting the response of the tumor to treatment (6)(7)(8)(9). Several commonly used chemotherapeutic agents, including those commonly used for ovarian cancer such as paclitaxel and gemcitabine, induce immunoreactive effects such as promotion of tumor antigen presentation through upregulating the expression of tumor antigens or MHC class I molecules (10,11). Other agents decrease the number of immunosuppressive cells, such as regulatory T cells or myeloid derived suppressor cells (MDSC), thereby increasing helper T-cell accumulation at the tumor site (7,8).…”

Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments

“…vincristine, vinblastine and paclitaxel) on DC maturation was further confi rmed by Shurin and colleagues [ 67 ]. Finally, Wan et al recently showed that both paclitaxel and vinblastine induced elevated expression of MHC class I molecule and increased secretion of IFN-β by breast cancer cells [ 68 ].…”