The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling

Abstract

The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumorassociated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8 + T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STINGdependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…PERK ablation led to a reprogramming of MDSC functionality, specifically, to initiate a type I interferon anti-tumor response. More importantly, similar anti-tumor effects can be achieved with the exogenous administration of PERK inhibitors ( 166 ).…”

“…Recent studies have attempted to explain why tumor-associated immunosuppressive myeloid cells cannot simply be binned in an M1/M2-like dichotomy, and Mohamed et al ( 166 ) describe ER stress as a potential mechanism. Undefined tumoral signaling causes an upregulation in the unfolded protein response of MDSCs, leading to an activation of the intermediate media PERK and NRF2 drive the immunoregulatory phenotype.…”

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

“…ER stress induced the expression of TNF-related apoptosis-induced ligand receptors (DR5) and lectin-type oxidized LDL receptor 1 (LOX1) and the conversion of neutrophils to polymorphonuclear MDSCs. The reduced NRF2 signalling favoured the accumulation of cytosolic mitochondrial DNA and consequent expression of antitumour type I interferon, in a STING-dependent manner 97 . …”

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

“…The deletion of PERK or treatment with the selective inhibitor of PERK AMG-44 reduces Nrf2 transcription, resulting in ROS overexpression, causing mitochondrial damage, impeding the immunosuppression of MDSCs, and increasing the infiltration of CD8 + T cells. This situation can be antagonized by the addition of the Nrf2 inducer sulforaphane [98]. According to the above report, it can be concluded that Nrf2overexpression and deletion affect the immunoinhibitory activity of MDSCs.…”

“…Treatment with Nrf2-inducing triterpenoids, such as omaveloxolone (RTA-408), CDDO-Me (RTA-402), and CDDO-Im (RTA-403), increases the transcriptional activity of Nrf2, which attenuates the production of ROS, abrogates the immune suppressive effect of MDSCs, and protects immune cells and tissues from oxidative stress [95][96][97]. However, a recent study has demonstrated that Nrf2 is activated by PKR-like endoplasmic reticulum (ER) kinase (PERK) in tumor-infiltrating MDSCs, giving MDSCs the potential for immunosuppression [98]. The deletion of PERK or treatment with the selective inhibitor of PERK AMG-44 reduces Nrf2 transcription, resulting in ROS overexpression, causing mitochondrial damage, impeding the immunosuppression of MDSCs, and increasing the infiltration of CD8 + T cells.…”