TY - JOUR
T1 - Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer
AU - Tcyganov, Evgenii N.
AU - Hanabuchi, Shino
AU - Hashimoto, Ayumi
AU - Campbell, David
AU - Kar, Gozde
AU - Slidel, Timothy W.F.
AU - Cayatte, Corinne
AU - Landry, Aimee
AU - Pilataxi, Fernanda
AU - Hayes, Susana
AU - Dougherty, Brian
AU - Hicks, Kristin C.
AU - Mulgrew, Kathy
AU - Tang, Chih Hang Anthony
AU - Hu, Chih Chi Andrew
AU - Guo, Wei
AU - Grivennikov, Sergei
AU - Ali, Mohammed Alkhatim A.
AU - Beltra, Jean Christophe
AU - Wherry, E. John
AU - Nefedova, Yulia
AU - Gabrilovich, Dmitry I.
N1 - Funding Information:
We thank Randal Kaufman (Sanford Brigham Prebys) and Deyu Fang (Northwestern University) for providing IRE1α × LysM-Cre mice, and the AstraZeneca Production Informatics team for performing RNAseq read alignment and qualification. This work was supported by NIH grants R01CA100062, RO1CA216936, R01CA163910, R01CA227629, and CA218133, and the Wistar Institute Animal and Flow cytometry core facilities under Cancer Center support grant P30 CA010815.
Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/8/16
Y1 - 2021/8/16
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI145971
DO - 10.1172/JCI145971
M3 - Article
C2 - 34228641
AN - SCOPUS:85113158578
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 16
M1 - e145971
ER -