Publications by authors named "Glenn Dranoff"

151 Publications

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.

Sci Rep 2021 01 14;11(1):1399. Epub 2021 Jan 14.

Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-80999-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809281PMC
January 2021

Chimeric Antigen Receptor T Cells Targeting NKG2D-Ligands Show Robust Efficacy Against Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia.

Front Immunol 2020 15;11:580328. Epub 2020 Dec 15.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, United States.

CAR T cell approaches to effectively target AML and T-ALL without off-tumor effects on healthy myeloid or T cell compartments respectively are an unmet medical need. NKG2D-ligands are a promising target given their absence on healthy cells and surface expression in a wide range of malignancies. NKG2D-ligand expression has been reported in a substantial group of patients with AML along with evidence for prognostic significance. However, reports regarding the prevalence and density of NKG2D-ligand expression in AML vary and detailed studies to define whether low level expression is sufficient to trigger NKG2D-ligand directed CART cell responses are lacking. NKG2D ligand expression in T-ALL has not previously been interrogated. Here we report that NKG2D-ligands are expressed in T-ALL cell lines and primary T-ALL. We confirm that NKG2D-ligands are frequently surface expressed in primary AML, albeit at relatively low levels. Utilizing CAR T cells incorporating the natural immune receptor NKG2D as the antigen binding domain, we demonstrate striking activity of CAR T cells targeting NKG2D-ligands against AML and T-ALL cell lines and show that even low-level ligand expression in primary AML targets results in robust NKG2D-CAR activity. We found that NKG2D-ligand expression can be selectively enhanced in low-expressing AML cell lines and primary AML blasts pharmacologic HDAC inhibition. Such pharmacologic NKG2D-ligand induction results in enhanced NKG2D-CAR anti-leukemic activity without affecting healthy PBMC, thereby providing rationale for the combination of HDAC-inhibitors with NKG2D-CAR T cell therapy as a potential strategy to achieve clinical NKG2D-CAR T cell efficacy in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.580328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769813PMC
June 2021

An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity.

Cell Chem Biol 2021 06 16;28(6):802-812.e6. Epub 2020 Dec 16.

Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address:

The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chembiol.2020.11.012DOI Listing
June 2021

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.

Nat Commun 2020 12 9;11(1):6315. Epub 2020 Dec 9.

Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA, 02139, USA.

Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19920-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725805PMC
December 2020

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy.

Cancer Immunol Res 2021 01 11;9(1):34-49. Epub 2020 Nov 11.

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing-related molecules in a cell type-specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell-engaging CD3-bispecific antibody therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-20-0080DOI Listing
January 2021

GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation.

Immunity 2019 04;50(4):796-811

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. Electronic address:

The β common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the β common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2019.03.022DOI Listing
April 2019

Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity.

J Immunother Cancer 2019 02 6;7(1):32. Epub 2019 Feb 6.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models.

Methods: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras GEMM of lung adenocarcinoma model.

Results: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro.

Conclusions: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-019-0504-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366094PMC
February 2019

Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

Nat Med 2019 Mar;25(3):529

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

In the version of this article originally published, the figure callout in this sentence was incorrect: "Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f)." The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825406PMC
March 2019

Identification and characterization of an alternative cancer-derived PD-L1 splice variant.

Cancer Immunol Immunother 2019 Mar 18;68(3):407-420. Epub 2018 Dec 18.

Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-018-2284-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428600PMC
March 2019

Drug Discovery for Kinetoplastid Diseases: Future Directions.

ACS Infect Dis 2019 02 13;5(2):152-157. Epub 2018 Dec 13.

Novartis Institute for Tropical Diseases (NITD) , 5300 Chiron Way , Emeryville , California 94608 , United States.

Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsinfecdis.8b00298DOI Listing
February 2019

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma.

Cancer Immunol Res 2019 01 5;7(1):100-112. Epub 2018 Nov 5.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 10-3 × 10 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3 T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells , but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-18-0307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814996PMC
January 2019

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

Background: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.

Methods: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up.

Results: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response.

Conclusions: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment.

Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623.

Funding: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.59125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237460PMC
October 2018

FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors.

Cancer Immunol Res 2018 12 28;6(12):1472-1485. Epub 2018 Sep 28.

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in the composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAPPDPN population of CAFs and a FAPPDPN population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFβ signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAPPDPN CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner, whereas FAPPDPN pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-18-0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597261PMC
December 2018

Manufacturing development and clinical production of NKG2D chimeric antigen receptor-expressing T cells for autologous adoptive cell therapy.

Cytotherapy 2018 07 29;20(7):952-963. Epub 2018 Jun 29.

Harvard Medical School, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Electronic address:

Background Aims: Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor (CAR)-modified T cells has demonstrated preclinical efficacy in several model systems, including hematological and solid tumors. We present comprehensive data on manufacturing development and clinical production of autologous NKG2D CAR T cells for treatment of acute myeloid leukemia and multiple myeloma (ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates with native costimulatory molecule DAP10, effectively generating a second-generation CAR against multiple ligands upregulated during malignant transformation including MIC-A, MIC-B and the UL-16 binding proteins.

Methods: CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells were genetically modified with replication-defective gamma-retroviral vector and expanded ex vivo for 5 days with recombinant human interleukin-2.

Results: Despite sizable interpatient variation in originally collected cells, release criteria, including T-cell expansion and purity (median 98%), T-cell transduction (median 66% CD8 T cells), and functional activity against NKG2D ligand-positive cells, were met for 100% of healthy donors and patients enrolled and collected. There was minimal carryover of non-T cells, particularly malignant cells; both effector memory and central memory cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated.

Conclusions: The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2018.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127861PMC
July 2018

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

Nat Med 2018 09 13;24(9):1459-1468. Epub 2018 Aug 13.

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0135-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129206PMC
September 2018

PPARγ Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF.

Cancer Immunol Res 2018 06 18;6(6):723-732. Epub 2018 Apr 18.

Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of in lysozyme M (LysM)-expressing myeloid cells (KO) showed a decreased ratio of CD8 T effectors to Tregs and impaired tumor rejection with GVAX. Diminished tumor protection was associated with altered DC responses and increased production of the Treg attracting chemokines CCL17 and CLL22. Correspondingly, the systemic administration of PPARγ agonists to vaccinated mice elevated the CD8 T effector to Treg ratio through effects on myeloid cells and intensified the antitumor activity of GVAX combined with cytotoxic T lymphocyte-associated antigen-4 antibody blockade. PPARγ agonists similarly attenuated Treg induction and decreased CCL17 and CCL22 levels in cultures of human peripheral blood mononuclear cells with GM-CSF-secreting tumor cells. Together, these results highlight a key role for myeloid cell PPARγ in GM-CSF-stimulated antitumor immunity and suggest that PPARγ agonists might be useful in cancer immunotherapy. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-17-0612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422646PMC
June 2018

Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.

Science 2018 Mar;359(6383):1537-1542

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aao0505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626532PMC
March 2018

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma.

Clin Cancer Res 2018 09 7;24(17):4175-4186. Epub 2018 Feb 7.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as , exhaustion among T cells infiltrating human and murine GBM. Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-1846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081269PMC
September 2018

Immunophenotyping of pediatric brain tumors: correlating immune infiltrate with histology, mutational load, and survival and assessing clonal T cell response.

J Neurooncol 2018 Apr 10;137(2):269-278. Epub 2018 Jan 10.

Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.

There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation. This was compared to the standard method of immunohistochemistry (IHC) for immune markers for 89 primary pediatric brain tumors. Both flow cytometry and IHC data did not correlate with the grade of tumor or mutational load and IHC data was not significantly associated with survival for either low grade or high grade gliomas. There is a trend towards a more immunosuppressive phenotype in higher grade tumors with more regulatory T cells present in these tumor types. Both PD1 and PDL1 were present in only a small percentage of the tumor infiltrate. T cell receptor sequencing revealed up to 10% clonality of T cells in tumor infiltrates and no significant difference in clonality between low and high grade gliomas. We have shown the immune infiltrate of pediatric brain tumors does not appear to correlate with grade or survival for a small sample of patients. Further research and larger studies are needed to fully understand the interaction of pediatric brain tumors and the immune system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-017-2737-9DOI Listing
April 2018

Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT.

Blood Adv 2017 Nov 14;1(24):2269-2279. Epub 2017 Nov 14.

Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA.

We report a clinical trial testing vaccination of autologous myeloblasts admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with ≥5% marrow blasts underwent myeloblast collection before HSCT. At approximately day +30, 6 vaccines composed of irradiated autologous myeloblasts mixed with GM-K562 were administered. Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was not tapered until vaccine completion (∼day 100). Thirty-three patients with AML (25) and MDS (8) enrolled, 16 (48%) had ≥5% marrow blasts at transplantation. The most common vaccine toxicity was injection site reactions. One patient developed severe eosinophilia and died of eosinophilic myocarditis. With a median follow-up of 67 months, cumulative incidence of grade 2-4 acute and chronic GVHD were 24% and 33%, respectively. Relapse and nonrelapse mortality were 48% and 9%, respectively. Progression-free survival (PFS) and overall survival (OS) at 5 years were 39% and 39%. Vaccinated patients who were transplanted with active disease (≥5% marrow blasts) had similar OS and PFS at 5 years compared with vaccinated patients transplanted with <5% marrow blasts (OS, 44% vs 35%, respectively, = .81; PFS, 44% vs 35%, respectively, = .34). Postvaccination antibody responses to angiopoietin-2 was associated with superior OS (hazard ratio [HR], 0.43; = .031) and PFS (HR, 0.5; = .036). Patients transplanted with active disease had more frequent angiopoeitin-2 antibody responses (62.5% vs 20%, = .029) than those transplanted in remission. GM-K562/leukemia cell vaccination induces biologic activity, even in patients transplanted with active MDS/AML. This study is registered at www.clinicaltrials.gov as #NCT 00809250.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017009084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737123PMC
November 2017

IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells.

Cancer Immunol Res 2018 01 29;6(1):25-35. Epub 2017 Nov 29.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-17-0490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754232PMC
January 2018

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Infection.

mBio 2017 10 24;8(5). Epub 2017 Oct 24.

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF) are highly susceptible to infection with , and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4 T cells as the infection progresses. -specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an macrophage infection model, we demonstrate that GM-CSF inhibition of growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against is the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response to While gamma interferon (IFN-γ) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-γ production alone is not sufficient to control In this study, we demonstrate that CD4, CD8, and nonconventional T cells produce GM-CSF during infection in mice and in the peripheral blood of infected humans. Under conditions where other sources of GM-CSF are absent, T cell production of GM-CSF is protective and is required for control of infection. GM-CSF activation of macrophages to limit bacterial growth requires host expression of the transcription factor PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01514-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654932PMC
October 2017

Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes.

Mol Cancer Res 2017 12 29;15(12):1722-1732. Epub 2017 Aug 29.

Novartis Institute for Biomedical Research, Shanghai, China.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 () locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature. This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-17-0134DOI Listing
December 2017

Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.

Cancer Immunol Res 2017 06 18;5(6):480-492. Epub 2017 May 18.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-16-0329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642913PMC
June 2017

Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade.

J Thorac Oncol 2017 08 6;12(8):1268-1279. Epub 2017 May 6.

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. Electronic address:

Introduction: Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses.

Methods: We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional Kras and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors.

Results: Tumors in IL-17:Kras mice grew more rapidly, resulting in a significantly shorter survival as compared with that of Kras mice. IL-6, granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein, and C-X-C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor-associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:Kras mice as compared with in Kras mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:Kras tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:Kras tumors resulted in a clinical response associated with T-cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL-17A and colony- stimulating factor 3 and a significant correlation among high neutrophil and lower T-cell numbers.

Conclusions: Here we have shown that an increase in a single cytokine, IL-17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine and neutrophil depletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2017.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532066PMC
August 2017

Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses.

J Exp Med 2017 06 4;214(6):1679-1690. Epub 2017 May 4.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti-PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20160831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460993PMC
June 2017

Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes.

Cancer Immunol Res 2017 06 4;5(6):446-454. Epub 2017 May 4.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-16-0385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509159PMC
June 2017

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

Nat Commun 2017 04 7;8:14922. Epub 2017 Apr 7.

Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms14922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385585PMC
April 2017
-->