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Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer
Evgenii N. Tcyganov, … , Yulia Nefedova, Dmitry I. Gabrilovich
Evgenii N. Tcyganov, … , Yulia Nefedova, Dmitry I. Gabrilovich
Published July 6, 2021
Citation Information: J Clin Invest. 2021;131(16):e145971. https://doi.org/10.1172/JCI145971.
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Research Article Immunology Oncology Article has an altmetric score of 1

Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer

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Abstract

Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity in different conditions is controlled by similar mechanisms. We compared MDSCs in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic MDSCs (M-MDSCs) but did not induce polymorphonuclear MDSCs (PMN-MDSCs). In contrast, both MDSC populations were present in cancer models. An acquisition of immune-suppressive activity by PMN-MDSCs in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in an increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSCs in cancer and LCMV infection. Acquisition of immune-suppressive activity by M-MDSCs in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSCs in tumor tissues. Suppressive activity of M-MDSCs in tumors was retained due to the effect of IL-6 present at high concentrations in the tumor site. These results demonstrate disease- and population-specific mechanisms of MDSC accumulation and the need for targeting different pathways to achieve inactivation of these cells.

Authors

Evgenii N. Tcyganov, Shino Hanabuchi, Ayumi Hashimoto, David Campbell, Gozde Kar, Timothy W.F. Slidel, Corinne Cayatte, Aimee Landry, Fernanda Pilataxi, Susana Hayes, Brian Dougherty, Kristin C. Hicks, Kathy Mulgrew, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A. Ali, Jean-Christophe Beltra, E. John Wherry, Yulia Nefedova, Dmitry I. Gabrilovich

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Figure 7

IFN-γ regulates suppressive activity of splenic M-MDSCs during chronic LCMV infection.

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IFN-γ regulates suppressive activity of splenic M-MDSCs during chronic L...
(A) C57BL/6 mice were infected with LCMV-Arm or LCMV-C13 and the concentrations of plasma IFN-γ were measured at different time points by ELISA. The results of 2 independent (n = 9) experiments are shown. (B–E) IFN-γR2fl/fl LysM-Cre positive and negative littermate mice (IFN-γR2ΔMyel and IFN-γR2fl/fl, respectively) were infected with LCMV-C13. Monocytic cells were sorted from spleens on day 14 and their suppressive activity was measured in cocultures with activated OT.1 splenocytes (B). Splenic CD8+ T cell responses to specific LCMV-derived peptide (gp33-41) were measured by IFN-γ intracellular staining (C) or IFN-γ ELISPOT (D). The gene expression of the key immunosuppressive molecules was measured in monocytic cells by qRT-PCR (E). The results of 3 independent experiments are shown (n = 5–6). *P < 0.05, **P < 0.01, ***P < 0.001 from control in 2-sided unpaired Student’s t tests. (F) Effect of iNOS inhibitor on the suppressive activity of M-MDSCs. Mice were infected with 1 × 106 pfu LCMV C13 strain i.v. and splenic monocytes were sorted on day 14. Suppression assay with sorted monocytes and OT.1 splenocytes was set up in the presence of vehicle or 700 μM L-NMMA. Mean and SD are shown (n = 3–4). P values were calculated using Student’s t tests.

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