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 9

Effect of TME on immune-suppressive activity of M-MDSCs with deleted IFN-γR2.

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Effect of TME on immune-suppressive activity of M-MDSCs with deleted IFN...
(A and B) Splenic M-MDSCs from LLC TB mice were sorted and cultured in the specified conditions for 24 hours. Their suppressive activity was measured with activated OT.1 splenocytes. The results of 3 independent experiments are shown; n = 3–5. (C) IL-6 protein concentrations in spleens and tumor lysates from LLC TB mice were measured by ELISA (n = 5). P value was calculated using 2-sided unpaired Student’s t tests. (D and E) LLC TB mice were treated with 400 μg/mL anti-IL6R or isotype control starting from day 3 every 3 days until day 16. (D) Kinetics of tumor growth were measured. Mean and SD (n = 6–10 per group) are shown. P values were calculated using 2-way ANOVA test. (E) Tumor monocytes from IFN-γR2ΔMyel mice (left panel) or WT mice (right panel) (n = 4 isotype-treated group, n = 6 IL-6R antibody–treated group) were sorted and suppressive activity was measured in triplicates with OT.1 splenocytes using 3H-thymidine incorporation. Proportion of proliferation from control values (splenocytes stimulated in the absence of MDSCs) is shown. P values were calculated using Student’s t test. (F) Inhibition of T cell proliferation by MDSCs generated from HPCs. Bone marrow HPCs were cultured for 3 days with GM-CSF and IL-6, then medium was replaced with a new medium with or without IL-6. Cells were collected 3 days later and incubated with splenocytes from PMEL mice in the presence of 10 ng/mL cognate gp100-derived peptide at 2:1 and 1:1 ratios. Cell proliferation was measured after 48 hours; n = 3. P values were calculated using unpaired 2-sided Student’s t tests. (G) Splenocytes isolated from PMEL mice were cultured with 10 ng/mL cognate gp100-derived peptide in the presence of different concentrations of IL-6 (0.02–20 ng/mL). Proliferation of T cells was measured after 48 hours.