Myeloid-derived suppressor cells (MDSC) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity at different conditions is controlled by similar mechanisms. We compared MDSC in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic - M-MDSC but did not induce polymorphonuclear - PMN-MDSC. In contrast, both MDSC populations were present in cancer models. An acquisition of immune suppressive activity by PMN-MDSC 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 increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSC in cancer and LCMV infection. Acquisition of immune suppressive activity by M-MDSC in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSC in tumor tissues. Suppressive activity of M-MDSC in tumors was retained due to the effect of IL-6 present at high concentrations in tumor site. These results demonstrate disease and population-specific mechanisms of MDSC accumulation and need for targeting of different pathways to achieve inactivation of these cells.
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 A. Tang, Chih-Chi A. Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A. Ali, Jean-Christophe Beltra, E. John Wherry, Yulia Nefedova, Dmitry I. Gabrilovich