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

doi:10.1016/j.immuni.2020.03.004

. 2020 Apr 14;52(4):668-682.e7.

doi: 10.1016/j.immuni.2020.03.004.

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

Eslam Mohamed¹, Rosa A Sierra¹, Jimena Trillo-Tinoco², Yu Cao¹, Patrick Innamarato¹, Kyle K Payne¹, Alvaro de Mingo Pulido¹, Jessica Mandula¹, Shuzhong Zhang³, Paul Thevenot⁴, Subir Biswas¹, Sarah K Abdalla¹, Tara Lee Costich¹, Kay Hänggi¹, Carmen M Anadon¹, Elsa R Flores⁵, Eric B Haura⁵, Shikhar Mehrotra⁶, Shari Pilon-Thomas¹, Brian Ruffell¹, David H Munn⁷, Juan R Cubillos-Ruiz⁸, Jose R Conejo-Garcia¹, Paulo C Rodriguez⁹

Affiliations

¹ Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
² Bristol-Myers Squibb, Devens, MA 01434, USA.
³ Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁴ Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
⁵ Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
⁷ Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
⁸ Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
⁹ Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: Paulo.Rodriguez@Moffitt.org.

PMID: 32294407
PMCID: PMC7207019
DOI: 10.1016/j.immuni.2020.03.004

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

Eslam Mohamed et al. Immunity. 2020.

. 2020 Apr 14;52(4):668-682.e7.

doi: 10.1016/j.immuni.2020.03.004.

Authors

Affiliations

¹ Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
² Bristol-Myers Squibb, Devens, MA 01434, USA.
³ Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁴ Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
⁵ Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
⁷ Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
⁸ Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
⁹ Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: Paulo.Rodriguez@Moffitt.org.

PMID: 32294407
PMCID: PMC7207019
DOI: 10.1016/j.immuni.2020.03.004

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 tumor-associated 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, STING-dependent 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.

Keywords: ER stress; MDSCs; NRF2; PERK; STING; tumor immunity; type I IFN; unfolded protein responses.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1.. TME drives immunosuppressive function and UPR activation in MDSC**
(A) Proliferation assessed by flow cytometry in CFSE-labeled T cells primed with anti-CD3 and anti-CD28 and co-cultured for 72 hours with S-MDSC or T-MDSC from mice bearing LLC (left), B16 (middle) or ID8-*Defb29-Vegfa* (right) tumors; or from splenic iMC from tumor-free mice (1:1/4 ratio). Sample from 3 independent repeats. (B) Immunoblot for the UPR sensors in iMC, S-MDSC, and T-MDSC from (A). Results are representative of 3 independent studies. (C) Sample of ER-Tracker compared to fluorescence minus one (FMO) from 3 distinct repeats (left) and merged mean fluorescence intensity data (MFI, right) in iMC, S-MDSC, or T-MDSC from LLC-bearing mice. (D) Transmission electron microscopy image from 3 independent repeats from cells as in (C) (left). Arrows indicate ER. Scale bar, 2 μm (upper) and 200 nm (lower). Quantification of data (right). (E-F) BM-MDSC derived using G-CSF and GM-CSF (20 ng/ml each) and in the presence of LLC-TES (30%) or Thaps (200 nM, 24 hours) were tested for the UPR drivers (E) or capacity block T cell proliferation (ratio 1:1/8) (F). Immunoblot and suppression assay are representative of 3 distinct repeats. (G-H) Human-MDSC derived using GM-CSF and IL-6 (10 ng/ml each) and in the presence of 10–60% supernatants from the 786–0 cell line or Thaps were tested for the expression of UPR drivers (G) or ability to blunt primed T cell proliferation (ratio 2:1) (H). Immunoblot and histograms are representative from 5 independent repeats. Statistics were done using one-way ANOVA or Student’s t-test. *, p<0.05; **, p<0.01. Please also see Figure S1.

**Figure 2.. TUDCA overcomes MDSC-related T cell dysfunction and boosts immunotherapy**
(A) Tumor volume ± SEM in mice bearing LLC (left) or B16 (right) cells and treated daily after day 6 post-tumor injection with vehicle or TUDCA (250 mg/kg). n=10. (B) Proliferation of primed CFSE-labelled T cells co-cultured with tumor-MDSC (ratio 1:1/4) from LLC-bearing mice treated with vehicle or TUDCA. n=5. (C) Immunoblot for NOS2 and Arginase I in tumor-MDSC from (A). n=3 independent repeats. (D) Percentage of CD69⁺CD44⁺ in CD8⁺ TILs from tumors as in (A) at day 15. n=5. (E) LLC tumor volume ± SEM in wildtype (WT) and *Rag1*^−/− mice treated as in (A). n=5. (F) Tumor volume ± SEM in mice bearing LLC (*left*) or B16 (*right*) tumors treated as in (A) and receiving or not 250 μg anti-Gr1 every 3^rd day since the day of tumor injection. n=5. (G-H) Percentage of CD69⁺CD44⁺ (G) and EGSRNQDWL-H-2D^b tetramer⁺ (H) in CD8⁺ TILs from B16-bearing mice treated as in (F). (I) B16 tumor volume ± SEM in mice treated as in (A) and receiving or not 250 μg anti-PD-L1. n=10. (J) Mice bearing EG7 tumors were treated as in (A) and specific cohorts received CD8⁺ OT-I T cells pre-primed with OVA_257–264. Tumor volume ± SEM. n=5. (K) Spleens from (J) tested for IFNγ by EliSpot upon priming with OVA_257–264. n=3 repeats of 3 spleens/group. (L) Tumor volume ± SEM for EG7 or LLC tumors injected s.c. in opposite flanks of mice that previously rejected EG7 tumors after TUDCA plus ACT treatment. n=3. Statistics were applied using one-way ANOVA or student’s t-test, *, p<0.05; **, p<0.01. Please also see Figure S2.

**Figure 3.. PERK intrinsically controls MDSC function**
(A) Left: Illustrative image of 46 Met-NSCLC tumors and 8 healthy control lung tissues from a TMA (20x resolution and further 10x digital magnification) showing phospho-PERK (Magenta), CD11b (Red), CD15 (Yellow), CD14 (Green), HLA-DR (Orange), pan-Cytokeratin (pCK, Cyan), and DAPI (Blue) by Automated Multispectral Imaging. Center: Sample histogram from samples from left showing pPERK expression on pCK^negCD11b⁺HLA-DR^neg cells from MET-NSCLC and control lungs. Right: Phospho-PERK⁺ cells ± SEM in PMN-MDSC-LC (pCK^negCD11b⁺HLA-DR^negCD14^negCD15⁺) or M-MDSC-LC (pCK^negCD11b⁺HLA-DR^negCD14⁺CD15^neg). n=8 control lung tissues and 46 MET-NSCLC tumors. (B) LLC *(lef*t, n=20) and B16 *(right*, n=10) tumor growth ± SEM in *Eif2ak3*^fl/fland *Eif2ak3*^fl/flLyz2-cre mice. (C) Growth of flank sarcoma initiated after injection with Cre recombinase-coding adenovirus in flank of *Kras*^G12D/+*Trp53*^fl/fl mice previously reconstituted with bone marrow from *Eif2ak3*^fl/flLyz2-cre or *Eif2ak3*^fl/fl mice. n=4. (D) Proliferation of primed CFSE-labeled T cells co-cultured with tumor-MDSC (ratio 1:1/4) from LLC-bearing control or PERK-null mice. Results are representative from 3 independent experiments. (E) Immunoblots for NOS2 and Arginase I (*left*) and UPR mediators in LLC tumor-MDSC from (D). Representative from 3 distinct experiments. (F) Control and *Eif2ak3*^−/−BM-MDSC pre-treated or not with Thaps (24 hours) were co-cultured with primed-T cells. T cell proliferation was assessed as in (D). n=4. (G-I) Percentage of CD8⁺ TILs in CD45⁺ cells (G); and CD69⁺CD44⁺ (H) and IFNγ⁺ cells (I) in CD8⁺ TILs in LLC tumors as in (B). n=5. (J) LLC growth ± SEM in *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice treated with 400 μg anti-CD8 antibody or isotype. n=5 mice/group. (K) Tumor volume ± SEM in B16-bearing mice treated with vehicle or AMG-44 (12, 24 mg/kg) daily after day 6 post-tumor injection. n=5. (L) Proliferation of primed T cells co-cultured with tumor-MDSC (ratio 1:1/4) from B16-bearing mice treated with vehicle or AMG-44 (12 mg/kg). n=3. (M) Frequency of IFNγ⁺ in CD8⁺ TILs from B16-bearing mice treated as in (L). n=4. (N) B16 growth ± SEM in mice treated as in (L) and with or without 250 μg anti-PD-L1. n=5. (O) Proliferation of primed T cells co-cultured with control or Thaps-treated BM-MDSC (ratio 1:1/8) pre-exposed to 5 μM AMG-44. n=3. Statistics were by one-way ANOVA, Student’s t-test, or log-rank (Mantel-Cox)*, p<0.05; **, p<0.01. Please also see Figure S3.

**Figure 4.. PERK deletion functionally reprograms tumor-MDSC**
(A-B) LLC volume ± SEM in *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice treated every 3^rd day with 250 μg anti-Gr1 (A), 250 μg anti-CCL2 (B) or IgG starting on the day of tumor injection. n=5. (C) Tumor growth in WT (*left*) and *Rag1*^−/− (*right*) mice injected with LLC cells alone or co-injected at a 1:1 ratio with LLC-tumor-MDSC from *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice. n=5. (D) Relative expression heatmap of specific markers on tumor MDSC subsets from LLC-bearing *Eif2ak3*^fl/flLyz2-cre mice compared to *Eif2ak3*^fl/fl mice. n=10. Arbitrary units. (E) Percentage of IL-12 (*left*) and TNF-α (*right*) in MDSC subsets from (D). n=3. (F) Illustrative from 3 independent experiments showing proliferation of CFSE-labeled OT-I CD8⁺ T cells co-cultured with LLC-MDSC from *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice, pre-loaded with 1 mg/ml OVA (16 hours). Control OT-I cell proliferation was induced by OVA-loaded DCs. (G-H) Merged MFI ± SEM (*left*) and sample histogram expression (*right*) of ZsGreen (G) and OVA-bound H-2K^b (H) in tumor-MDSC from Pan02-Ova-ZsGreen-bearing *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice. n=5 (G) and n= 8 (H). (I) Percentage of SIINFEKL-H-2K^b-tetramer⁺ in CD8⁺ TILs from Pan02-Ova-ZsGreen tumors from *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice. n=4. (J-K) Fold MFI change of ZsGreen (J) and SIINFEKL-bound H-2k^b (K) in tumor-associated myeloid subsets from *Eif2ak3*^fl/flLyz2-cre mice relative to controls. MFI values of specific myeloid subsets from PERK-null mice were divided over those from control mice. n=5 (L) Proliferation of cell-trace violet-labeled OT-I T cells co-cultured with tumor-MDSC (ratio 1:1/4) from (G). As positive control, OT-1 cells were co-cultured with GM-CSF plus IL-4-induced DCs loaded with OV_A257–264 (1:1/4). Representative from 3 distinct repeats. Statistics applied using one-way ANOVA or Student’s t-test, *, p<0.05; **, p<0.01. Please also see Figure S4.

**Figure 5.. Functional switch of PERK-null MDSC occurs through impaired NRF2 signaling**
(A) Immunoblot of CHOP in tumor-MDSC from *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice bearing LLC tumors. Sample of n=5 distinct tumors. (B) Proliferation of primed CFSE-labelled T cells co-cultured with wild type (WT), *Eif2ak3*^−/− or *Ddit3*^−/− BM-MDSC pre-treated or not with Thaps (24 hours) (ratio 1:1/8). n=3. (C) Control and *Eif2ak3*^−/− BM-MDSC were transduced with lentivirus expressing *Ddit3* (*Ddit3*-OE) or control (control-OE), after which they were treated with or without Thaps (24 hours) and co-cultured with primed-T cells (ratio 1/8:1). T cell proliferation assessed as in (B). n=3. (D-E) NRF2 immunoblot (D) and NRF2 binding to a consensus DNA-binding sequence (E) using 15 μg nuclear extracts from tumor-MDSC from LLC-bearing *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice. n=3 from distinct experiments. (F) DCFDA in control MDSC (left), Thaps-treated BM-MDSC (middle), or tumor-MDSC (right) from controls and PERK-null mice. Illustrative result from 3 distinct experiments. (G) Proliferation of activated T cells co-cultured for 72 hours with control or *Eif2ak3*^−/− BM-MDSC pre-treated for 3 hours with vehicle, Resveratrol, or Sulforaphane (SFRN) and Thaps for 24 hours. n=3 (H) Proliferation of primed T cells co-cultured with BM-MDSC transduced with lentivirus coding for NRF2-ΔNeh2 or control and treated with Thaps (24 hours). n=3. (I) Tumor Volume ± SEM in *Eif2ak3*^fl/fl or *Eif2ak3*^fl/flLyz2-cre mice bearing LLC-tumors and treated with vehicle or SFRN n=5. (J) Percentages of DCFDA⁺ MDSC in tumors from (I). n=3. (K) Percentage of proliferating T cells co-cultured with MDSC (ratio 1:1/4) from tumors from (I). n=4. Statistics were applied using one-way ANOVA or student’s t-test, *, p<0.05; **, p<0.01, ***, p<0.001. Please also see Figure S5.

**Figure 6.. NRF2 regulates mitochondrial homeostasis in PERK-null MDSC**
(A) Transmission electron microscopy image of tumor-MDSC from LLC-bearing *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice. Arrow heads point to mitochondria. Scale bar, 500 nm. Representative result from 3 independent experiments. (B) Illustrative histogram of 3 distinct repeats (upper) and merged MFI values (lower) of Mitotracker fluorescence in tumor-MDSC from (A). (C) Histogram of aggregated JC-1 fluorescence (*upper*) and JC-1 aggregates: JC-1 monomers ratio (*upper*) in tumor-MDSC from (A). n=3 independent repeats. (D) Oxygen consumption rate (OCR) after mitochondrial stress analysis in tumor-MDSC from LLC-bearing *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice. n=5. (E) OCR as in (D) in control and *Eif2ak3*^−/− BM-MDSC transduced with NRF2-ΔNeh2 or control carrying lentivirus and treated with Thaps (24 hours). n=3. (F) OCR as in (D) in tumor-MDSC from *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice bearing LLC tumors and treated with vehicle or SFRN. n=3. (G-H) Relative *Cox1* and *Nd1* DNA expression in mitochondria-free cytosolic fractions (G) and mitochondrial-enriched fractions (H) from tumor-MDSC from (A). Results are triplicates of 5 samples/group. (I) Proliferation of T cells co-cultured with Control and *Eif2ak3*^−/− BM-MDSC developed in the presence of 150 ng/ml of EtBr and treated with or without Thaps (24 hours). n=3. Statistics were applied using student’s t-test, *, p<0.05; **, p<0.01. Please also see Figure S6.

**Figure 7.. STING-dependent Type I IFN regulates functional switch of PERK-null MDSC**
(A) Illustrative immunoblot from 3 independent experiments showing cytosolic phospho-TBK1 (pTBK1) and total TBK1, or nuclear phospho-IRF3 (pIRF3) and IRF3 in LLC-tumor MDSC from *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice. (B) Tumor Volume ± SEM in *Lyz2-cre*, *Eif2ak3*^fl/flLyz2-cre, *Tmem173* ^fl/flLyz2-cre, and *Eif2ak3*^fl/fl *Tmem173* ^fl/flLyz2-cre (*Eif2ak3*-*Tmem173* ^−/−) mice bearing LLC tumors for 15 days. n=7. (C) Proliferation of primed CFSE-labeled T cells cultured with tumor-MDSC from (B) (ratio 1:1/4). n=3. (D) Percentage of IFNγ⁺ in CD8⁺ TILs from (B). n=4. (E) Tumor-draining lymph nodes from *Lyz2-cre*, *Eif2ak3*^fl/flLyz2-cre, *Tmem173* ^fl/flLyz2-cre and *Eif2ak3*-*Tmem173* ^−/− mice bearing Pan02-Ova-ZsGreen tumors for 14 days were tested for IFNγ by EliSpot upon OVA_257–264 activation. n=3/group. (F) Proliferation of cell-trace violet-labeled OT-I CD8⁺ T cells co-cultured with tumor-MDSC from mice from (B). Sample of 5 independent repeats. (G) Relative expression of *Infb1*, *Ifit3*, *Cxcl10*, mRNA in tumor-MDSC from (B). Duplicates from 5 samples/group. (H) Tumor volume ± SEM in LLC-bearing *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice treated or not every 3 days with 1 mg anti-IFNAR1 antibody from day of tumor injection. n=5. (I) Relative *Ifnb1* mRNA expression in control and *Eif2ak3*^−/− BM-MDSC developed in the presence of 150 ng/ml of EtBr and treated with Thaps (24 hours). n= 3. (J) Relative *Ifnb1* mRNA in control and *Eif2ak3*^−/− BM-MDSC transduced with lentivirus coding for NRF2-ΔNeh2 or control and then treated with Thaps (24 hours). (K) Relative *Ifnb1* mRNA expression in LLC tumor-MDSC from *Eif2ak3*^fl/fl and *Eif2ak3*^fl/flLyz2-cre mice treated with vehicle or SFRN. Statistics were applied using one-way ANOVA, *, p<0.05; **, p<0.01. Please also see Figure S7.

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Reducing Stress PERKs up Anti-tumor Immunity.
Charbonneau ME, O'Riordan MXD. Charbonneau ME, et al. Immunity. 2020 Apr 14;52(4):575-577. doi: 10.1016/j.immuni.2020.03.012. Immunity. 2020. PMID: 32294402 Free PMC article.

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References

1. Ahn J, Son S, Oliveira SC, and Barber GN (2017). STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. Cell Rep 21, 3873–3884. - PMC - PubMed
1. Ahn J, Xia T, Konno H, Konno K, Ruiz P, and Barber GN (2014). Inflammation-driven carcinogenesis is mediated through STING. Nat Commun 5, 5166. - PMC - PubMed
1. Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, et al. (2013). Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73, 1993–2002. - PubMed
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[1] Ahn J, Son S, Oliveira SC, and Barber GN (2017). STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. Cell Rep 21, 3873–3884. - PMC - PubMed

[2] Ahn J, Son S, Oliveira SC, and Barber GN (2017). STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. Cell Rep 21, 3873–3884. - PMC - PubMed

[3] Ahn J, Xia T, Konno H, Konno K, Ruiz P, and Barber GN (2014). Inflammation-driven carcinogenesis is mediated through STING. Nat Commun 5, 5166. - PMC - PubMed

[4] Ahn J, Xia T, Konno H, Konno K, Ruiz P, and Barber GN (2014). Inflammation-driven carcinogenesis is mediated through STING. Nat Commun 5, 5166. - PMC - PubMed

[5] Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, et al. (2013). Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73, 1993–2002. - PubMed

[6] Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, et al. (2013). Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73, 1993–2002. - PubMed

[7] Bettigole SE, and Glimcher LH (2015). Endoplasmic reticulum stress in immunity. Annu Rev Immunol 33, 107–138. - PubMed

[8] Bettigole SE, and Glimcher LH (2015). Endoplasmic reticulum stress in immunity. Annu Rev Immunol 33, 107–138. - PubMed

[9] Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, and Glimcher LH (2015). The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol 16, 829–837. - PMC - PubMed

[10] Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, and Glimcher LH (2015). The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol 16, 829–837. - PMC - PubMed

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

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

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