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Tumor derived stress triggers C/EBPβ homologous protein (Chop) expression in myeloid derived suppressor cells (MDSC) and mediates immunosuppressive activity
© Thevenot et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Suppression of anti-tumor T cell responses by MDSC remains a significant barrier in cancer immunotherapy. Although several pathways have been characterized as critical for MDSC-induced suppression, there are currently no therapies to globally and specifically inhibit MDSC function. We postulate that identifying and inhibiting the central mediators of MDSC-regulatory activity will overcome T cell suppression and increase the efficacy of T cell-based immunotherapy in cancer. We aimed to determine the role of the common stress sensor C/EBP-homologous-stress-related protein (Chop), a downstream product of integrated stress responses, as a master regulator of MDSC-suppressive activity. Our results show that Chop is preferentially expressed in malignant cells and MDSC in s.c. mouse tumors. Selective expression of Chop was also detected in tumor-infiltrating MDSC from colon carcinoma patients. Interestingly, injection of tumor cells having functional Chop into systemic Chop -/- mice or Chop null bone marrow chimeric mice resulted in a significant anti-tumor effect mediated by CD8+ T cells, suggesting the importance of MDSC-Chop in tumor-induced tolerance. In fact, deletion of Chop in MDSC increased the efficacy of T cell-based immunotherapy. MDSC isolated from tumor-bearing Chop null mice had decreased ability to block T cell responses; impaired expression of major MDSC-inhibitory pathways; and a surprising ability to prime T cell proliferation and induce anti-tumor effects. Accordingly, depletion of Gr-1+ MDSC restored tumor growth in Chop -/- mice, while it prevented tumor growth in wild type mice, confirming functional differences in MDSC from wild type and Chop -/- mice. To therapeutically block Chop in tumors, we used a specific liposomal-encapsulated siRNA, which successfully blocked Chop expression and induced anti-tumor effects. We next examined the effects of Chop on C/EBPβ and STAT-3, both master regulators of MDSC function. MDSC from Chop -/- mice had elevated expression of C/EBPβ inhibitory isoform LIP, low C/EBPβ binding to IL-6-promoter, decreased IL-6 production, and impaired expression of IL-6 target phospho-STAT-3. Also, Chop -/- MDSC expressed higher levels of miR-142-3p, a mi-RNA that promotes C/EBPβ LIP over LAP and LAP*. Ectopic expression of IL-6 in tumors restored tumor growth, MDSC suppression, and C/EBPβ and phospho-STAT-3 levels in Chop -/- mice, suggesting the role of this pathway in the effects induced by Chop deletion. Collectively, this data suggests the role of Chop as a master regulator of the immune inhibitory activity of MDSC and justify the potential targeting of Chop as a way to restore protective immunity in cancer.
Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.