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 6

IRE1α and ATF6 deletion in myeloid cells improves antigen-specific responses and delays the growth of MC38 tumors.

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IRE1α and ATF6 deletion in myeloid cells improves antigen-specific respo...
(A) MC38 tumor growth in mice with specified deletions. The representative results of 1 of 2 independent experiments are shown; n = 5 for Cre– control and n = 6 mice for IRE1αΔMyel mice, n = 5 for control and n = 6 for CHOP-KO mice, n = 19 for Cre– control, and n = 15 for ATF6ΔMyel mice. P values are from 2-way ANOVA test with adjustments for multiple measurements. (B) MC38 tumor growth in IRE1αΔMyel and ATF6ΔMyel mice treated with 100 μg anti-CD8 antibody twice per week starting from day 1; n = 8 for control and n = 4 for treated IRE1αΔMyel mice, n = 4 for control, and n = 4 for treated ATF6ΔMyel mice. (C) Antigen-specific response to KYMCNSSCM p53 peptide by splenic CD8+ T cells from IRE1αΔMyel, CHOP–/–, and ATF6ΔMyel mice bearing MC38 tumors was measured by IFN-γ ELISPOT; n = 3–8. Individual values are shown on graph. P values calculated with Mann-Whitney U tests are shown on graphs. (D) Expression of genes associated with suppressive activity was evaluated by qRT-PCR in tumor PMN-MDSCs isolated from IRE1αΔMyel LLC TB mice. The results of 3 independent experiments are shown; n = 4 and individual values are shown on graphs. *P < 0.05. (E) Expression of genes associated with suppressive activity was evaluated by qRT-PCR in spleen PMN-MDSCs isolated from IRE1αΔMyel LLC TB mice. P value was calculated using 2-sided unpaired Student’s t tests; n = 4–5 and individual values are shown on graphs. (F) Spleen and tumor PMN-MDSCs from ATF6ΔMyel MC38 TB CD8 antibody-treated mice with similar tumor sizes and IRE1αΔMyel LLC TB mice with similar tumor sizes were sorted and cultured for 20 hours. Supernatants were collected and the amount of PGE2 was measured by ELISA; n = 4–13. Individual values are shown on graphs. P values calculated from 2-sided Student’s t tests are shown.