Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment

Klement, John D.; Redd, Priscilla S.; Lu, Chunwan; Merting, Alyssa D.; Poschel, Dakota B.; Yang, Dafeng; Savage, Natasha M.; Zhou, Gang; Munn, David H.; Fallon, Padraic G.; Liu, Kebin

doi:10.1016/j.ccell.2023.02.005

Cited by 60 publications

(35 citation statements)

References 81 publications

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“…Given the function of PD-L1 as a potent inhibitor of T cells in the tumor microenvironment 1–3,5 , our above observation that PD-L1 KO tumor has increased T cell accumulation is expected. We then analyzed T cell subpopulations in the single cell level.…”

Section: Resultsmentioning

confidence: 88%

“…CT26 cell line was obtained from ATCC (Manassas, VA). MC38-met cells were as previously described 5 . All cells were cultured in RPMI1640 medium with 10% FBS at 37 0 C in 5% CO2 incubator.…”

Section: Methodsmentioning

confidence: 99%

“…PD-L1 also binds to PD-1 expressed on myeloid cells to reprogram myeloid cell metabolism to promote differentiation of myeloid-derived suppressor cells 4 and to repress IRF8-dependent myeloid cell differentiation, resulting in suppression of T cell activation 3 . Furthermore, PD-L1 engages myeloid cell PD-1 to activate the SHP2-type I interferon (IFN)-STAT1-CXCL9 pathway to impair CTL tumor recruitment 5 . The PD-(L)1 pathway therefore acts as an immune checkpoint that negatively regulates T cell activation and tumor recruitment to promote tumor immune escape.…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Poschel,

Klement,

Merting

et al. 2023

Preprint

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PD-L1 functions as a suppressor of T cell activation and colonic inflammation. The consequence of and mechanism underlying these opposite functions of PD-L1 in colorectal cancer remains unknown. We report that global Cd274 deletion promotes inflammation-driven colorectal tumorigenesis. 16S rRNA and shotgun metagenomic sequencing revealed that loss of host PD-L1 leads to expansion of gut Ligilactobacillus murinus and activation of the AhR pathway in tumor-bearing mice. scRNA-seq analysis revealed that PD-L1 regulates PD-1hiNrp1lo Treg, IL6+ neutrophils, and B cells in colorectal tumor. Treg expresses high level of TGFβ to recruit IL6+ neutrophils. IL6 inhibits activation of B and T cells. IL6 blockade or B cell activation via CD40 agonist increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 functions as a tumor suppressor in the context of inflammation-driven colorectal cancer and the PD-L1/L. murius/PD-1hiNrp1loTGFβ+ Treg/IL6+ neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis.

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Section: Resultsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Poschel,

Klement,

Merting

et al. 2023

Preprint

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“…Tang et al 145 these therapies induce significant changes across innate and adaptive cell types both locally and in the draining lymph node. 131,[148][149][150][151] These discoveries suggest that cell therapies should also be designed to broadly restructure the endogenous immune system to elicit a greater antitumor efficacy.…”

Section: Directly Targeting the Axes Of Immunosuppressionmentioning

confidence: 99%

Toward the clinical development of synthetic immunity to cancer

Garcia

Burnett

Roybal

2023

Immunological Reviews

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SummarySynthetic biology (synbio) tools, such as chimeric antigen receptors (CARs), have been designed to target, activate, and improve immune cell responses to tumors. These therapies have demonstrated an ability to cure patients with blood cancers. However, there are significant challenges to designing, testing, and efficiently translating these complex cell therapies for patients who do not respond or have immune refractory solid tumors. The rapid progress of synbio tools for cell therapy, particularly for cancer immunotherapy, is encouraging but our development process should be tailored to increase translational success. Particularly, next‐generation cell therapies should be rooted in basic immunology, tested in more predictive preclinical models, engineered for potency with the right balance of safety, educated by clinical findings, and multi‐faceted to combat a range of suppressive mechanisms. Here, we lay out five principles for engineering future cell therapies to increase the probability of clinical impact, and in the context of these principles, we provide an overview of the current state of synbio cell therapy design for cancer. Although these principles are anchored in engineering immune cells for cancer therapy, we posit that they can help guide translational synbio research for broad impact in other disease indications with high unmet need.

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“…26−28 Tumor cells may use programmed death-ligand 1 (PD-L1) to activate the programmed cell death protein 1 (PD-1)-Src homology domain 2 containing tyrosine phosphatase (SHP2) immune suppressive pathway to repress IFN-I expression to impair cytotoxic T lymphocytes (CTLs) tumor infiltration and function, resulting in tumor immune evasion and progression. 29 Restoring IFN-I expression and production in the tumor microenvironment therefore represents an effective approach in reversing immune suppression and enhancing CTLs tumor infiltration and function to repress tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer

Yang,

Bo,

Liang

et al. 2024

ACS Nano

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Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells. IFN-I activates the expression of Cxcl9 and Cxcl10 to enhance T cell tumor infiltration. RNA-Seq detected a low level of IFNα13 and IFNβ in colon tumor tissue. scRNA-Seq revealed that IFNβ is expressed in immune cell subsets in non-neoplastic human tissues and to a lesser degree in human colon tumor tissues. Forced expression of IFNα13 and IFNβ in colon tumor cells upregulates major histocompatibility complex I (MHC I) expression and suppresses colon tumor growth in vivo. In human cancer patients, IFNβ expression is positively correlated with human leukocyte antigen (HLA) expression, and IFN-I signaling activation correlates with the patient response to PD-1 blockade immunotherapy. To translate this finding to colon cancer immunotherapy, we formulated a 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol-encapsulated IFNβencoding plasmid (IFNBCOL01). IFNBCOL01 transfects colon tumor cells to express IFNβ to increase the level of MHC I expression. IFNBCOL01 therapy transfects tumor cells and tumor-infiltrating immune cells to produce IFNβ to activate MHC I and granzyme B expression and inhibits colon tumor growth in mice. Our data determine that lipid nanoparticle delivery of IFNβ-encoding plasmid DNA enhances tumor immunogenicity and T cell effector function to suppress colon tumor growth in vivo.

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Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment

Cited by 60 publications

References 81 publications

PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Toward the clinical development of synthetic immunity to cancer

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer

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Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment

Cited by 60 publications

References 81 publications

PD-L1 Restrains the PD-1hiNrp1loTGFβ+Treg to block IL6+Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

PD-L1 Restrains the PD-1hiNrp1loTGFβ+Treg to block IL6+Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

Toward the clinical development of synthetic immunity to cancer

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer

Contact Info

Product

Resources

About

PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

PD-L1 Restrains the PD-1^hiNrp1^loTGFβ⁺Treg to block IL6⁺Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer