Publications by authors named "Mautin Hundeyin"

21 Publications

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Is dilution the solution in gastric cancer?

Lancet Gastroenterol Hepatol 2021 02 27;6(2):85-86. Epub 2020 Nov 27.

Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30339-3DOI Listing
February 2021

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

J Gastrointest Surg 2021 07;25(7):1885-1895

Department of General Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.
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http://dx.doi.org/10.1007/s11605-020-04551-4DOI Listing
July 2021

General surgery chief residents' perspective on surgical education during the coronavirus disease 2019 (COVID-19) pandemic.

Surgery 2020 08 11;168(2):222-225. Epub 2020 Jun 11.

Department of Surgery, Veterans Affairs Boston Healthcare System, MA; Department of Surgery Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Background: The coronavirus disease 2019 pandemic has negatively affected the training of general surgery chief residents during the last trimester of their residency. Our goal was to evaluate the educational concerns of graduating general surgery chief residents during the coronavirus disease 2019 pandemic.

Methods: An anonymous web-based survey was distributed between March 31 and April 7, 2020 to all current general surgery chief residents from 6 academic medical centers in Boston, Massachusetts. Interviews were also conducted with attending surgeons from participating institutions.

Results: A total of 24 of 39 general surgery chief residents participated in our survey (61.5% response rate). General surgery chief residents were most concerned about the potential delay in the date of board examinations, followed by not feeling adequately prepared for the board examinations and a possible delay in the graduation date. Whereas not having enough cases to feel ready for fellowship or job and not achieving a sufficient number of cases to meet the requirements for graduation were only moderately concerning to chief residents, attending surgeons stressed a greater importance on the loss of the operative experience as nearly all (93.3%) of them suggested a personalized approach for additional general surgery training during fellowship or job onboarding.

Conclusion: In addition to the dramatic impact on public health, the coronavirus disease 2019 outbreak has also caused unprecedented changes to surgical education. Therefore, creative interventions are needed to help general surgery chief residents successfully transition into the next phase of their surgical career.
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http://dx.doi.org/10.1016/j.surg.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287487PMC
August 2020

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Nat Immunol 2020 04 9;21(4):442-454. Epub 2020 Mar 9.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4 T cells, which prevented activation, reduced T1-polarization and directed T17-differentiation. PD-L1 signaling also induced an anergic T-betIFN-γ phenotype in CD8 T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 T cells engaged PD-1 macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 T cells have diverse tolerogenic effects on tumor immunity.
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http://dx.doi.org/10.1038/s41590-020-0620-xDOI Listing
April 2020

The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.

Nature 2019 10 2;574(7777):264-267. Epub 2019 Oct 2.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA). However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.
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http://dx.doi.org/10.1038/s41586-019-1608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858566PMC
October 2019

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.

Hepatology 2020 02 31;71(2):477-494. Epub 2019 Dec 31.

Department of Surgery, S.A. Localio Laboratory, New York University School of Medicine, New York, NY.

Background And Aims: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH).

Approach And Results: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4 , PD1 , Ly6C CD44 phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution.

Conclusions: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4 T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.
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http://dx.doi.org/10.1002/hep.30952DOI Listing
February 2020

Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

Cancer Discov 2019 09 2;9(9):1288-1305. Epub 2019 Jul 2.

Department of Medicine, New York University School of Medicine, New York, New York.

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβCD4CD8NK1.1 innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17 cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4 and CD8 T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726581PMC
September 2019

Specialized dendritic cells induce tumor-promoting IL-10IL-17 FoxP3 regulatory CD4 T cells in pancreatic carcinoma.

Nat Commun 2019 03 29;10(1):1424. Epub 2019 Mar 29.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA.

The drivers and the specification of CD4 T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T-program. Specifically, CD11bCD103 DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 tumor-promoting IL-10IL-17IFNγregulatory CD4 T cells. The balance between this distinctive T program and canonical FoxP3T is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11bCD103 DC promote CD4 T cell tolerance in PDA which may underscore its resistance to immunotherapy.
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http://dx.doi.org/10.1038/s41467-019-09416-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441038PMC
March 2019

Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis.

Oncogene 2019 06 11;38(23):4512-4526. Epub 2019 Feb 11.

S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA.

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFα CD206 phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.
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http://dx.doi.org/10.1038/s41388-019-0734-5DOI Listing
June 2019

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.

Cancer Cell 2018 11;34(5):757-774.e7

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA.

Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIITNFαIFNγ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
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http://dx.doi.org/10.1016/j.ccell.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836726PMC
November 2018

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.

Cancer Discov 2018 04 22;8(4):403-416. Epub 2018 Mar 22.

Department of Biology, Brooklyn College and the Graduate Center (CUNY), Brooklyn, New York, New York.

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4 T cells and CD8 T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225783PMC
April 2018

NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.

J Exp Med 2017 06 25;214(6):1711-1724. Epub 2017 Apr 25.

S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4 T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8 T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3 hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
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http://dx.doi.org/10.1084/jem.20161707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461004PMC
June 2017

Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.

Nat Med 2017 May 10;23(5):556-567. Epub 2017 Apr 10.

S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.

The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4 and CD8 T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
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http://dx.doi.org/10.1038/nm.4314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419876PMC
May 2017

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.

Cell 2016 Sep 25;166(6):1485-1499.e15. Epub 2016 Aug 25.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. Electronic address:

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.
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http://dx.doi.org/10.1016/j.cell.2016.07.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017923PMC
September 2016

Mincle Signaling Promotes Con A Hepatitis.

J Immunol 2016 10 24;197(7):2816-27. Epub 2016 Aug 24.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016; Department of Cell Biology, New York University School of Medicine, New York, NY 10016

Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.
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http://dx.doi.org/10.4049/jimmunol.1600598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026929PMC
October 2016

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

Nature 2016 Apr 6;532(7598):245-9. Epub 2016 Apr 6.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
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http://dx.doi.org/10.1038/nature17403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833566PMC
April 2016

Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

Gastroenterology 2016 06 3;150(7):1659-1672.e5. Epub 2016 Mar 3.

Department of Surgery, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York; Department of Cell Biology, S Arthur Localio Laboratory, New York University School of Medicine, New York, New York. Electronic address:

Background & Aims: The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci.

Methods: We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry.

Results: Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth.

Conclusions: Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth.
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http://dx.doi.org/10.1053/j.gastro.2016.02.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909514PMC
June 2016

Mincle suppresses Toll-like receptor 4 activation.

J Leukoc Biol 2016 07 8;100(1):185-94. Epub 2016 Jan 8.

Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, New York, NY, USA; and Department of Cell Biology, S. Arthur Localio Laboratory, New York University School of Medicine, New York, NY, USA

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation.
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http://dx.doi.org/10.1189/jlb.3A0515-185RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608084PMC
July 2016
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