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

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

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 8

IFN-γ regulates suppressive activity of splenic M-MDSCs during tumor progression.

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IFN-γ regulates suppressive activity of splenic M-MDSCs during tumor pro...
(A) IFN-γ concentration in sera, spleens, and tumor lysates from naive and LLC TB mice were measured by ELISA. The results of 3 independent experiments are shown (n = 3–8). (B and C) IFN-γR2ΔMyel and IFN-γR2fl/fl mice were injected with LLC (B) or MC38 (C) tumor cells and the tumor growth kinetics were measured. The representative results of 1 of 3 similar experiments are shown (n = 9 for IFN-γR2fl/fl and n = 4 for IFN-γR2ΔMyel mice in LLC model, n = 6 for IFN-γR2fl/fl, and n = 4 for IFN-γR2ΔMyel mice in MC38 model). M-MDSCs and PMN-MDSCs were sorted from spleens and tumors. Their suppressive activity was measured in cocultures with activated OT.1 splenocytes (D) and the expression of the key immunosuppressive molecules in M-MDSCs was measured by qRT-PCR (E) (n = 4–5 from 2 independent experiments). **P < 0.01; ***P < 0.001 from control using 2-sided Student’s t tests.