Immunology, Microenvironment, and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
AstraZeneca, Gaithersburg, Maryland, USA.
J Clin Invest. 2021 Aug 16;131(16). doi: 10.1172/JCI145971.
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.
髓系来源的抑制细胞（MDSCs）是癌症和慢性感染中免疫反应的主要负调控因子。目前尚不清楚在不同条件下调节 MDSC 活性是否受相似机制控制。我们比较了癌症和淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染小鼠中的 MDSC。慢性 LCMV 感染导致单核细胞 MDSC（M-MDSC）的发展，但不会诱导多形核 MDSC（PMN-MDSC）。相比之下，这两种 MDSC 群体都存在于癌症模型中。PMN-MDSC 在癌症中的免疫抑制活性的获得受内质网（ER）应激反应的 IRE1α 和 ATF6 途径控制。通过阻断 ER 应激反应阻断 PMN-MDSC 活性导致肿瘤特异性免疫反应增加和肿瘤进展减少。相比之下，ER 应激反应对于癌症和 LCMV 感染中 M-MDSC 的抑制活性是可有可无的。IFN-γ 信号转导介导了脾脏中 M-MDSC 的免疫抑制活性获得。然而，它对于肿瘤组织中 M-MDSC 的抑制活性是可有可无的。由于肿瘤部位高浓度存在的 IL-6，M-MDSC 在肿瘤中的抑制活性得以保留。这些结果表明 MDSC 积累具有疾病和群体特异性机制，需要针对不同途径来实现这些细胞的失活。
