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

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 WherryYulia Nefedova, Dmitry I. Gabrilovich

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere145971
JournalJournal of Clinical Investigation
Volume131
Issue number16
DOIs
StatePublished - Aug 16 2021

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer'. Together they form a unique fingerprint.

Cite this