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Article ; Online: Hypoxia-activated prodrug and antiangiogenic therapies cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.

Liu, Arthur / Gammon, Seth T / Pisaneschi, Federica / Boda, Akash / Ager, Casey R / Piwnica-Worms, David / Hong, David S / Curran, Michael A

JCI insight

2024 Volume 9, Issue 1

Abstract: We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and ... ...

Abstract	We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast with prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8+ T cell response. Bulk tumor RNA sequencing, flow cytometry, and adoptive myeloid cell transfer suggested that treated tumor cells increased their capacity to recruit granulocytic myeloid-derived suppressor cells (G-MDSCs) through CCL9 secretion. Blockade of the CCL9/CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302, anti-VEGFR-2, and ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
MeSH term(s)	Humans ; Pancreatic Neoplasms/pathology ; Myeloid-Derived Suppressor Cells ; Adenocarcinoma/pathology ; Vascular Endothelial Growth Factor A/metabolism ; Hypoxia/metabolism
Chemical Substances	TH 302 ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.169150
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Article ; Online: Identification of Nonfunctional Alternatively Spliced Isoforms of STING in Human Acute Myeloid Leukemia.

Boda, Akash R / Liu, Arthur J / Castro-Pando, Susana / Whitfield, Benjamin T / Molldrem, Jeffrey J / Al-Atrash, Gheath / Di Francesco, Maria Emilia / Jones, Philip / Ager, Casey R / Curran, Michael A

Cancer research communications

2024 Volume 4, Issue 3, Page(s) 911–918

Abstract: Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro ... ...

Abstract	Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.
MeSH term(s)	Humans ; Protein Isoforms/genetics ; Leukemia, Myeloid, Acute/genetics ; Alternative Splicing/genetics ; Interferon Type I/genetics ; Cell Line ; Tumor Microenvironment
Chemical Substances	Protein Isoforms ; Interferon Type I
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-24-0095
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Article: KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Ager, Casey R / Zhang, Mingxuan / Chaimowitz, Matthew / Bansal, Shruti / Obradovic, Aleksandar / Rogava, Meri / Melms, Johannes C / McCann, Patrick / Spina, Catherine / Drake, Charles G / Dallos, Matthew C / Izar, Benjamin

bioRxiv : the preprint server for biology

2023

Abstract: Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow ... ...

Abstract	Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios
Language	English
Publishing date	2023-01-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.01.522340
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Article ; Online: KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Ager, Casey R / Zhang, Mingxuan / Chaimowitz, Matthew / Bansal, Shruti / Tagore, Somnath / Obradovic, Aleksandar / Jugler, Collin / Rogava, Meri / Melms, Johannes C / McCann, Patrick / Spina, Catherine / Drake, Charles G / Dallos, Matthew C / Izar, Benjamin

Journal for immunotherapy of cancer

2023 Volume 11, Issue 9

Abstract	Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios
MeSH term(s)	Humans ; CD4-Positive T-Lymphocytes ; T-Lymphocyte Subsets ; Carcinoma, Renal Cell ; Kidney Neoplasms ; Immunotherapy ; Biomarkers ; Receptors, Immunologic ; Lectins, C-Type
Chemical Substances	Biomarkers ; KLRG1 protein, human ; Receptors, Immunologic ; Lectins, C-Type
Language	English
Publishing date	2023-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-006782
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Article ; Online: Longitudinal Immune Profiling Reveals Unique Myeloid and T-cell Phenotypes Associated with Spontaneous Immunoediting in a Prostate Tumor Model.

Ager, Casey R / Obradovic, Aleksandar Z / Arriaga, Juan M / Chaimowitz, Matthew G / Califano, Andrea / Abate-Shen, Cory / Drake, Charles G

Cancer immunology research

2021 Volume 9, Issue 5, Page(s) 529–541

Abstract: The theory of cancer immunoediting, which describes the dynamic interactions between tumors and host immune cells that shape the character of each compartment, is foundational for understanding cancer immunotherapy. Few models exist that facilitate in- ... ...

Abstract	The theory of cancer immunoediting, which describes the dynamic interactions between tumors and host immune cells that shape the character of each compartment, is foundational for understanding cancer immunotherapy. Few models exist that facilitate in-depth study of each of the three canonical phases of immunoediting: elimination, equilibrium, and escape. Here, we utilized NPK-C1, a transplantable prostate tumor model that we found recapitulated the three phases of immunoediting spontaneously in immunocompetent animals. Given that a significant portion of NPK-C1 tumors reliably progressed to the escape phase, we were able to delineate cell types and mechanisms differentially prevalent in equilibrium versus escape phases. Using high-dimensional flow cytometry, we found that activated CD4
MeSH term(s)	Animals ; Antigens, CD/immunology ; CD8-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; Flow Cytometry ; Integrin alpha Chains/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Prostatic Neoplasms/immunology ; Prostatic Neoplasms/pathology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Burden/immunology ; Tumor Escape ; Tumor Microenvironment/immunology
Chemical Substances	Antigens, CD ; Integrin alpha Chains ; alpha E integrins
Language	English
Publishing date	2021-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-20-0637
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Article ; Online: TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma.

Reilley, Matthew J / Morrow, Brittany / Ager, Casey R / Liu, Arthur / Hong, David S / Curran, Michael A

Journal for immunotherapy of cancer

2019 Volume 7, Issue 1, Page(s) 323

Abstract: Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. ... ...

Abstract	Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. Tumor-resident myeloid cells and selected lymphocyte populations retain expression of Toll-like Receptors (TLR) that sense common features of pathogens and activate innate immunity in response. We explored whether agonists of TLR9 could augment innate immunity to promote tumor regression alone or in combination with T cell checkpoint blockade. In the setting of the immunogenic B16-Ova (Ovalbumin) expressing melanoma model, local injection of the CpG oligonucleotide TLR9 agonist ODN1826 combined with systemic CTLA-4 blockade cured 45% of mice of both their treated and an untreated tumor on the opposite flank demonstrating the synergistic potential of this combination. Next, in the non-immunogenic B16-F10 melanoma model, we showed that only intra-tumoral, but not systemic TLR9 activation augments the therapeutic potential of checkpoint blockade. In this setting, intra-tumoral TLR9 activation cooperated equally with either CTLA-4 or PD-1 blockade co-administered locally or given systemically; however, the uninjected tumor rarely regressed. Anti-CTLA-4 combinations were associated with improved intra-tumoral CD8 to regulatory T cell ratios, while anti-PD-1 combinations elicited improved ratios of CD8 T cells relative to suppressive myeloid stroma. Using both a TLR9 agonist (MGN1703) and a CTLA-4 antibody (9D9-IgG2a) of increased potency cured 50% of bi-lateral B16-F10 melanoma. These findings suggest that intra-tumoral TLR9 agonists can improve sensitivity of poorly immunogenic tumors to T cell checkpoint blockade, and that newer, higher potency TLR agonists and checkpoint antibodies can raise the therapeutic ceiling for this combination therapy.
MeSH term(s)	Animals ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use ; Biomarkers, Tumor ; CTLA-4 Antigen/antagonists & inhibitors ; Cytotoxicity, Immunologic ; Male ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma, Experimental ; Mice ; Oligodeoxyribonucleotides/pharmacology ; Prognosis ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Toll-Like Receptor 9/agonists ; Treatment Outcome
Chemical Substances	Antineoplastic Agents, Immunological ; Biomarkers, Tumor ; CTLA-4 Antigen ; Oligodeoxyribonucleotides ; Toll-Like Receptor 9
Language	English
Publishing date	2019-11-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1186/s40425-019-0811-x
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Article ; Online: Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy.

Ager, Casey R / Zhang, Huaping / Wei, Zhanlei / Jones, Philip / Curran, Michael A / Di Francesco, M Emilia

Bioorganic & medicinal chemistry letters

2019 Volume 29, Issue 20, Page(s) 126640

Abstract: Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-β) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In ...

Abstract	Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-β) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.
MeSH term(s)	Animals ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Antineoplastic Agents/chemistry ; Cell Line ; Cytosol/metabolism ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/pharmacology ; Humans ; Immunity, Innate ; Immunotherapy/methods ; Interferon-beta/metabolism ; Melanoma/immunology ; Melanoma, Experimental/immunology ; Membrane Proteins/immunology ; Mice ; Nucleotides, Cyclic/antagonists & inhibitors ; Phosphates/metabolism ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Antigens, Neoplasm ; Antineoplastic Agents ; Heterocyclic Compounds ; Membrane Proteins ; Nucleotides, Cyclic ; Phosphates ; Interferon-beta (77238-31-4) ; phosphorodithioic acid (8056RR93HU)
Language	English
Publishing date	2019-08-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2019.126640
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Zs.A 3203: Show issues

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Article ; Online: Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity.

Ager, Casey R / Reilley, Matthew J / Nicholas, Courtney / Bartkowiak, Todd / Jaiswal, Ashvin R / Curran, Michael A

Cancer immunology research

2017 Volume 5, Issue 8, Page(s) 676–684

Abstract: Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. ...

Abstract	Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint-modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen/antagonists & inhibitors ; CTLA-4 Antigen/immunology ; Cell Line, Tumor ; Cyclic GMP/immunology ; Dendritic Cells/immunology ; Humans ; Immunotherapy ; Lymphocytes, Tumor-Infiltrating/immunology ; Membrane Proteins/agonists ; Membrane Proteins/immunology ; Mice ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Programmed Cell Death 1 Receptor/immunology ; T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
Chemical Substances	CTLA-4 Antigen ; CTLA4 protein, human ; Membrane Proteins ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Sting1 protein, mouse ; TNFRSF9 protein, human ; Tumor Necrosis Factor Receptor Superfamily, Member 9 ; flt3 ligand protein ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2017-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-17-0049
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Zs.A 7022: Show issues

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Article ; Online: Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer.

Cancer cell

2023 Volume 41, Issue 11, Page(s) 1972–1988.e5

Abstract: When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in ... ...

Abstract	When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Androgen Antagonists/therapeutic use ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Androgens/therapeutic use ; Immunotherapy ; Castration ; Tumor Microenvironment
Chemical Substances	Androgen Antagonists ; Androgens
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.10.006
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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Article ; Online: High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege.

Ager, Casey R / Boda, Akash / Rajapakshe, Kimal / Lea, Spencer Thomas / Di Francesco, Maria Emilia / Jayaprakash, Priyamvada / Slay, Ravaen B / Morrow, Brittany / Prasad, Rishika / Dean, Meghan A / Duffy, Colm R / Coarfa, Cristian / Jones, Philip / Curran, Michael A

Journal for immunotherapy of cancer

2021 Volume 9, Issue 8

Abstract: Background: Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite ... ...

Abstract	Background: Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking. Methods: Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Results: Highly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach. Conclusions: This study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.
MeSH term(s)	Animals ; Humans ; Immunotherapy/methods ; Male ; Membrane Proteins/pharmacology ; Membrane Proteins/therapeutic use ; Mice ; Myeloid-Derived Suppressor Cells/metabolism ; Pancreatic Neoplasms/drug therapy
Chemical Substances	Membrane Proteins ; Sting1 protein, mouse
Language	English
Publishing date	2021-07-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-003246
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