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1.
Cancer Discov ; 11(7): 1792-1807, 2021 07.
Article in English | MEDLINE | ID: mdl-33632774

ABSTRACT

Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAF V600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAF V600E Lgr5 CreMin (BLM) mice, tumors have similarities to human BRAF V600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti-PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy. SIGNIFICANCE: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene-microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAF V600E Lgr5 CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.This article is highlighted in the In This Issue feature, p. 1601.


Subject(s)
Bacteroides fragilis/physiology , Colorectal Neoplasms/microbiology , Proto-Oncogene Proteins B-raf/genetics , Animals , Carcinogenesis , Cell Transformation, Neoplastic , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/therapy , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mutation
2.
mBio ; 13(1): e0299121, 2021 02 22.
Article in English | MEDLINE | ID: mdl-35130731

ABSTRACT

Fusobacteria are commonly associated with human colorectal cancer (CRC), but investigations are hampered by the absence of a stably colonized murine model. Further, Fusobacterium nucleatum subspecies isolated from human CRC have not been investigated. While F. nucleatum subspecies are commonly associated with CRC, their ability to induce tumorigenesis and contributions to human CRC pathogenesis are uncertain. We sought to establish a stably colonized murine model and to understand the inflammatory potential and virulence genes of human CRC F. nucleatum, representing the 4 subspecies, animalis, nucleatum, polymorphum, and vincentii. Five human CRC-derived and two non-CRC derived F. nucleatum strains were tested for colonization, tumorigenesis, and cytokine induction in specific-pathogen-free (SPF) and/or germfree (GF) wild-type and ApcMin/+ mice, as well as in vitro assays and whole-genome sequencing (WGS). SPF wild-type and ApcMin/+ mice did not achieve stable colonization with F. nucleatum, whereas certain subspecies stably colonized some GF mice but without inducing colon tumorigenesis. F. nucleatum subspecies did not form in vivo biofilms or associate with the mucosa in mice. In vivo inflammation was inconsistent across subspecies, whereas F. nucleatum induced greater cytokine responses in a human colorectal cell line, HCT116. While F. nucleatum subspecies displayed genomic variability, no distinct virulence genes associated with human CRC strains were identified that could reliably distinguish these strains from non-CRC clinical isolates. We hypothesize that the lack of F. nucleatum-induced tumorigenesis in our model reflects differences in human and murine biology and/or a synergistic role for F. nucleatum in concert with other bacteria to promote carcinogenesis. IMPORTANCE Colon cancer is a leading cause of cancer morbidity and mortality, and it is hypothesized that dysbiosis in the gut microbiota contributes to colon tumorigenesis. Fusobacterium nucleatum, a member of the oropharyngeal microbiome, is enriched in a subset of human colon tumors. However, it is unclear whether this genetically varied species directly promotes tumor formation, modulates mucosal immune responses, or merely colonizes the tumor microenvironment. Mechanistic studies to address these questions have been stymied by the lack of an animal model that does not rely on daily orogastric gavage. Using multiple murine models, in vitro assays with a human colon cancer cell line, and whole-genome sequencing analysis, we investigated the proinflammatory and tumorigenic potential of several F. nucleatum clinical isolates. The significance of this research is development of a stable colonization model of F. nucleatum that does not require daily oral gavages in which we demonstrate that a diverse library of clinical isolates do not promote tumorigenesis.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Animals , Humans , Mice , Carcinogenesis , Cytokines , Disease Models, Animal , Fusobacterium nucleatum/genetics , Inflammation/complications , Tumor Microenvironment
3.
Sci Transl Med ; 12(539)2020 04 15.
Article in English | MEDLINE | ID: mdl-32295900

ABSTRACT

Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyzed fibrotic capsules surrounding surgically excised human breast implants from 12 individuals. We found increased numbers of interleukin 17 (IL17)-producing γδ+ T cells and CD4+ T helper 17 (TH17) cells as well as senescent stromal cells in the fibrotic capsules. Further analysis in a murine model demonstrated an early innate IL17 response to implanted synthetic material (polycaprolactone) particles that was mediated by innate lymphoid cells and γδ+ T cells. This was followed by a chronic adaptive CD4+ TH17 cell response that was antigen dependent. Synthetic materials with varying chemical and physical properties implanted either in injured muscle or subcutaneously induced similar IL17 responses in mice. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to implanted synthetic materials and the development of p16INK4a senescent cells. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model. Discovery of a feed-forward loop between the TH17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response.


Subject(s)
Cellular Senescence , Foreign Bodies , Foreign-Body Reaction , Interleukin-17 , Animals , Female , Foreign Bodies/immunology , Humans , Immunity, Innate , Interleukin-17/metabolism , Mice , Mice, Inbred C57BL , Prostheses and Implants
4.
Clin Cancer Res ; 25(17): 5250-5259, 2019 Sep 01.
Article in English | MEDLINE | ID: mdl-31061070

ABSTRACT

PURPOSE: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. EXPERIMENTAL DESIGN: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti-PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. RESULTS: Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. CONCLUSIONS: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.See related commentary by Willis et al., p. 5185.


Subject(s)
Colorectal Neoplasms , DNA Mismatch Repair , Humans , Immunotherapy , Lymphocytes, Tumor-Infiltrating , Tumor Microenvironment
6.
J Immunother Cancer ; 7(1): 40, 2019 02 11.
Article in English | MEDLINE | ID: mdl-30744692

ABSTRACT

BACKGROUND: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. CASE PRESENTATION: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. CONCLUSIONS: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/drug therapy , Colorectal Neoplasms/immunology , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , T-Lymphocytes/immunology , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Mutation , Oncogenes , Treatment Outcome
7.
Mucosal Immunol ; 12(1): 164-177, 2019 01.
Article in English | MEDLINE | ID: mdl-30279518

ABSTRACT

Polysaccharide A (PSA), an immunogenic capsular component of non-toxigenic Bacteroides fragilis (NTBF) strain NCTC 9343, is reported to promote mucosal immune development and suppress colitis. Contrastingly, enterotoxigenic Bacteroides fragilis (ETBF) is highly associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), rapidly inducing IL-17-dependent murine colitis and tumorigenesis. In specific-pathogen-free (SPF) C57BL/6 wild-type (WT) and multiple intestinal neoplasia (MinApc716+/-) mice, we show that sequential treatment of the NTBF strain, 9343, followed by the ETBF strain, 86-5443-2-2 (86), diminished colitis and tumorigenesis. Mice treated simultaneously with 9343 and 86 exhibited both severe colitis and tumorigenesis. Abrogated disease severity in sequentially treated mice was attributed to 9343 strain dominance and decreased IL-17A, but 86 colonization prior to or simultaneous with 9343 mitigated the anti-inflammatory effect of 9343. Remarkably, 9343-mediated protection was independent of PSA, as sequentially treated mice receiving ΔPSA 9343 exhibited similar protection. Further, SPF WT and Min mice colonized with PSA-competent or PSA-deficient 9343 exhibited similar IL-10, IL-17, and IFN-γ responses. Treatment of 86-colonized mice with 9343 failed to disrupt 86 pathogenesis. Our findings demonstrate that 9343 colonization, independent of PSA, offers prophylaxis against colitis-inducing 86 but may not be a valid therapy once colitis is established.


Subject(s)
Bacteroides fragilis/immunology , Colitis/immunology , Colorectal Neoplasms/immunology , Inflammatory Bowel Diseases/immunology , Intestinal Mucosa/immunology , Th17 Cells/immunology , Adenomatous Polyposis Coli Protein/genetics , Animals , Bacteroides fragilis/pathogenicity , Carcinogenesis , Cells, Cultured , Colitis/chemically induced , Disease Models, Animal , Humans , Interleukin-17/metabolism , Lipopolysaccharides/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Trinitrobenzenesulfonic Acid
9.
Cell Host Microbe ; 23(2): 203-214.e5, 2018 Feb 14.
Article in English | MEDLINE | ID: mdl-29398651

ABSTRACT

Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.


Subject(s)
Bacterial Toxins/immunology , Bacteroides fragilis/immunology , Carcinogenesis/pathology , Colon/immunology , Colorectal Neoplasms/etiology , Epithelial Cells/immunology , Interleukin-17/immunology , Metalloendopeptidases/immunology , Transcription Factor RelA/metabolism , Adenomatous Polyposis Coli Protein/genetics , Animals , Bacterial Toxins/metabolism , Bacteroides fragilis/pathogenicity , Cell Line, Tumor , Colon/cytology , Colon/microbiology , Colorectal Neoplasms/microbiology , Colorectal Neoplasms/pathology , Enzyme Activation/immunology , Female , Gene Deletion , HT29 Cells , Humans , Inflammation/immunology , Inflammation/microbiology , Interleukin-17/genetics , Male , Metalloendopeptidases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/immunology , Receptors, Interleukin-17/genetics , Receptors, Interleukin-17/immunology , Receptors, Interleukin-8B/genetics , STAT3 Transcription Factor/metabolism
10.
Am J Physiol Gastrointest Liver Physiol ; 313(1): G39-G49, 2017 Jul 01.
Article in English | MEDLINE | ID: mdl-28428350

ABSTRACT

Copper-transporting ATPase 2 (ATP7B) is essential for mammalian copper homeostasis. Mutations in ATP7B result in copper accumulation, especially in the liver, and cause Wilson disease (WD). The major role of hepatocytes in WD pathology is firmly established. It is less certain whether the excess Cu in hepatocytes is solely responsible for development of WD. To address this issue, we generated a mouse strain for Cre-mediated deletion of Atp7b and inactivated Atp7b selectively in hepatocytes. Atp7bΔHep mice accumulate copper in the liver, have elevated urinary copper, and lack holoceruloplasmin but show no liver disease for up to 30 wk. Liver inflammation is muted and markedly delayed compared with the age-matched Atp7b-/- null mice, which show a strong type1 inflammatory response. Expression of metallothioneins is higher in Atp7bΔHep livers than in Atp7b-/- mice, suggesting better sequestration of excess copper. Characterization of purified cell populations also revealed that nonparenchymal cells in Atp7bΔHep liver maintain Atp7b expression, have normal copper balance, and remain largely quiescent. The lack of inflammation unmasked metabolic consequences of copper misbalance in hepatocytes. Atp7bΔHep animals weigh more than controls and have higher levels of liver triglycerides and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. By 45 wk, all animals develop liver steatosis on a regular diet. Thus copper misbalance in hepatocytes dysregulates lipid metabolism, whereas development of inflammatory response in WD may depend on copper status of nonparenchymal cells. The implications of these findings for the cell-targeting WD therapies are discussed.NEW & NOTEWORTHY Targeted inactivation of copper-transporting ATPase 2 (Atp7b) in hepatocytes causes steatosis in the absence of inflammation.


Subject(s)
Adenosine Triphosphatases/metabolism , Cation Transport Proteins/metabolism , Fatty Liver/etiology , Gene Expression Regulation/physiology , Hepatocytes/metabolism , Obesity/etiology , Adenosine Triphosphatases/genetics , Animals , Cation Transport Proteins/genetics , Copper-Transporting ATPases , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Liver/metabolism , Mice , Mice, Knockout
11.
Science ; 352(6283): 366-70, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-27081073

ABSTRACT

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair.


Subject(s)
Biocompatible Materials , Muscle, Skeletal/injuries , Muscle, Skeletal/physiology , Tissue Scaffolds , Wound Healing/immunology , Adaptive Immunity , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Disease Models, Animal , Homeostasis/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Macrophages/immunology , Mice, Inbred C57BL , Rapamycin-Insensitive Companion of mTOR Protein , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Th2 Cells/immunology , Tissue Engineering
12.
Cancer Res ; 76(8): 2115-24, 2016 04 15.
Article in English | MEDLINE | ID: mdl-26880802

ABSTRACT

IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.


Subject(s)
Adaptive Immunity , Colonic Neoplasms/pathology , Immunity, Innate , Interleukin-17/biosynthesis , Animals , CD4 Antigens/immunology , Carcinogenesis , Colonic Neoplasms/immunology , Colonic Neoplasms/metabolism , Humans , Mice , Mice, Inbred C57BL
13.
Cancer Discov ; 5(10): 1098-109, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26201900

ABSTRACT

UNLABELLED: Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3(DTR) mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis. SIGNIFICANCE: Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production.


Subject(s)
Bacteroides Infections/complications , Bacteroides fragilis/physiology , Cell Transformation, Neoplastic , Colonic Neoplasms/etiology , Colonic Neoplasms/metabolism , Interleukin-17/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Animals , Bacteroides Infections/microbiology , Colonic Neoplasms/pathology , Disease Models, Animal , Interleukin-2/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Lymphocyte Depletion , Mice , Mice, Transgenic , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
14.
Cancer Discov ; 5(1): 43-51, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25358689

ABSTRACT

UNLABELLED: We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8(+) cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five-PD-1, PD-L1, CTLA-4, LAG-3, and IDO-currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer. SIGNIFICANCE: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair-defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested.


Subject(s)
Cell Cycle Checkpoints , Colonic Neoplasms/genetics , Colonic Neoplasms/immunology , Microsatellite Instability , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Colonic Neoplasms/pathology , Humans , Immunohistochemistry , Immunophenotyping , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Phenotype , Stromal Cells/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
15.
Cancer Cell ; 25(5): 621-37, 2014 May 12.
Article in English | MEDLINE | ID: mdl-24823639

ABSTRACT

Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.


Subject(s)
Epithelial Cells/metabolism , Hematopoietic System/metabolism , Interleukin-17/metabolism , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Animals , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Carcinoma in Situ/prevention & control , Cell Transformation, Neoplastic , Chemoprevention , Hematopoietic System/cytology , Humans , Inflammation , Interleukin-17/antagonists & inhibitors , Interleukin-17/genetics , Mice , Mice, Transgenic , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/prevention & control , Receptors, Antigen, T-Cell, gamma-delta/biosynthesis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Interleukin-17/biosynthesis , Receptors, Interleukin-17/metabolism , Signal Transduction/genetics , Th17 Cells/immunology
16.
Cancer Res ; 69(16): 6607-14, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19679552

ABSTRACT

IFN-producing killer dendritic cells (IKDC) represent a recently discovered cell type in the immune system that possesses a number of functions contributing to innate and adaptive immunity, including production of type 1 and 2 IFNs, interleukin (IL)-12, natural killing, and ultimately antigen presentation to naïve T cells. Here, we compared in vitro and in vivo responses of mouse IKDC, conventional dendritic cells (DC), and natural killer (NK) cells to murine cytomegalovirus infection and found distinct functions among these cell subsets. Upon recognition of infected fibroblasts, IKDC, as well as NK, produced high level of IFN-gamma, but unlike NK, IKDC simultaneously produced IL-12p40 and up-regulated MHC class II (MHC-II) and costimulatory molecules. Using MHC-II molecule expression as a phenotypic marker to distinguish activated IKDC from activated NK, we further showed that highly purified MHC-II(+) IKDC but not NK cross-present MHC class I-restricted antigens derived from MCMV-infected targets to CD8(+) T cells in vitro and in vivo. Our findings emphasize the unique nature of IKDC as a killer antigen-presenting cell directly linking innate and adaptive immunity.


Subject(s)
Antigen-Presenting Cells/immunology , Cross-Priming/immunology , Dendritic Cells/immunology , Dendritic Cells/physiology , Interferons/metabolism , T-Lymphocytes/immunology , Animals , Antigen-Presenting Cells/metabolism , Cells, Cultured , Cytotoxicity, Immunologic/immunology , Dendritic Cells/metabolism , Interleukin-12/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, SCID , Myeloid Differentiation Factor 88/genetics
17.
Nat Med ; 12(2): 207-13, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16444266

ABSTRACT

Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.


Subject(s)
Dendritic Cells/immunology , Interferons/biosynthesis , Killer Cells, Natural/immunology , Adaptation, Physiological , Animals , Antigen Presentation , Cell Line, Tumor , Cytotoxicity, Immunologic , Dendritic Cells/classification , Dendritic Cells/ultrastructure , Gene Expression , Immunity, Innate , In Vitro Techniques , Killer Cells, Natural/classification , Killer Cells, Natural/ultrastructure , Listeria monocytogenes/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Mice, Transgenic , Oligodeoxyribonucleotides/pharmacology
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