TLR2 ligation protects effector T cells from regulatory T-cell mediated suppression and repolarizes T helper responses following MVA-based cancer immunotherapy.

Abstract:

:Cancer immunotherapy is hampered by the immunosuppression maintained by regulatory T cells (Tregs) in tumor-bearing hosts. Stimulation of the Toll-like receptor 2 (TLR2) by Pam3Cys is known to affect Treg-mediated suppression. We found that Pam3Cys increases the proliferation of both CD4(+) effector T cells (Teffs) and Tregs co-cultured in vitro, but did not induce the proliferation of Tregs alone upon CD3 and CD28 stimulation. In a mouse model of RMA-MUC1 tumors, Pam3Cys was administered either alone or in combination with a modified vaccinia ankara (MVA)-based mucin 1 (MUC1) therapeutic vaccine. The combination of Pam3Cys with MVA-MUC1 (1) diminished splenic Treg/CD4(+) T-cell ratios to those found in tumor-free mice, (2) stimulated a specific anti-MUC1 interferon γ (IFNγ) response and (3) had a significant therapeutic effect on tumor growth and mouse survival. When CD4(+) Teffs and Tregs were isolated from Pam3Cys-treated mice, Teffs had become resistant to Treg-mediated suppression while upregulating the expression of BclL-x(L). Tregs from Pam3Cys-treated mice were fully suppressive for Teffs from naïve mice. Bcl-x(L) was induced by Pam3Cys with different kinetics in Tregs and Teffs. Teff from Pam3Cys-treated mice produced increased levels of Th1 and Th2-type cytokines and an interleukin (IL)-6-dependent secretion of IL-17 was observed in Teff:Treg co-cultures, suggesting that TLR2 stimulation had skewed the immune response toward a Th17 profile. Our results show for the first time that in a tumor-bearing host, TLR2 stimulation with Pam3Cys affects both Tregs and Teffs, protects Teff from Treg-mediated suppression and has strong therapeutic effects when combined with an MVA-based antitumor vaccine.

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Amiset L,Fend L,Gatard-Scheikl T,Rittner K,Duong V,Rooke R,Muller S,Bonnefoy JY,Préville X,Haegel H

doi

10.4161/onci.21479

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

1271-1280

issue

8

eissn

2162-4011

issn

2162-402X

pii

2012ONCOIMM0232

journal_volume

1

pub_type

杂志文章
  • Metabolic perturbation sensitizes human breast cancer to NK cell-mediated cytotoxicity by increasing the expression of MHC class I chain-related A/B.

    abstract::Cleavage or shedding of the surface antigen, MHC class I chain-related (MIC) protein (A/B) has been known to be one of the mechanisms by which tumor cells escape host immune surveillance. Thus, any strategy to augment the surface expression of MICA/B could facilitate anticancer immune response. Here, we demonstrate th...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/2162402X.2014.991228

    authors: Fu D,Geschwind JF,Karthikeyan S,Miller E,Kunjithapatham R,Wang Z,Ganapathy-Kanniappan S

    更新日期:2015-01-14 00:00:00

  • Immunosurveillance in esophageal carcinoma: The decisive impact of regulatory T cells.

    abstract::Neoadjuvant radiochemotherapy of esophageal carcinomas causes a variable degree of depletion of tumor-infiltrating FOXP3+ regulatory T cells (Tregs). The frequency of local Tregs in the operative specimens negatively correlates with the pathological response and overall patient survival. These results underscore the i...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2015.1064581

    authors: Vacchelli E,Semeraro M,Adam J,Dartigues P,Zitvogel L,Kroemer G

    更新日期:2015-07-01 00:00:00

  • Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma.

    abstract::Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2016.1253657

    authors: Honda Y,Otsuka A,Ono S,Yamamoto Y,Seidel JA,Morita S,Hirata M,Kataoka TR,Takenouchi T,Fujii K,Kanekura T,Okubo Y,Takahashi K,Yanagi T,Hoshina D,Hata H,Abe R,Fujimura T,Funakoshi T,Yoshino K,Masuzawa M,Amoh Y,T

    更新日期:2016-11-04 00:00:00

  • Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia.

    abstract::The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we conducted a pilot clinical trial of autologous or donor- derived T cells genetically modified to express a CAR targeting the B-cell antigen CD19 harboring 4-1BB and ...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2015.1027469

    authors: Dai H,Zhang W,Li X,Han Q,Guo Y,Zhang Y,Wang Y,Wang C,Shi F,Zhang Y,Chen M,Feng K,Wang Q,Zhu H,Fu X,Li S,Han W

    更新日期:2015-05-26 00:00:00

  • Induction of immunogenic cell death by targeting RIG-I-like helicases in pancreatic cancer.

    abstract::RIG-I-like helicases (RLH) are cytosolic sensors for viral RNA inducing type I interferon production. We found that pancreatic cancer cells express functional RLH and are susceptible to RLH-induced apoptosis via intrinsic and extrinsic pathways. Tumor cells displayed features of immunogenic cell death resulting in den...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/21624011.2014.955687

    authors: Schnurr M,Duewell P

    更新日期:2014-12-13 00:00:00

  • TNFR2: The new Treg switch?

    abstract::Three recent publications identified the TNF/TNR2 pathway as a new target to reduce graft-versus-host-disease through regulatory T cells activation or to potentially switch on a strong anti-leukemic effect through regulatory T cells blockade in allogeneic hematopoietic stem cell transplantation. This identified the TN...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1373236

    authors: Cohen JL,Wood KJ

    更新日期:2017-09-21 00:00:00

  • Lenalidomide enhances myeloma-specific T-cell responses in vivo and in vitro.

    abstract::Immunomodulation is an important part of lenalidomide's mode of action. We analyzed the impact of lenalidomide on T cells from patients with multiple myeloma during lenalidomide therapy in vivo and in patients with lenalidomide-refractory disease in vitro Patients enrolled in the German Speaking Myeloma Multicenter Gr...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2016.1139662

    authors: Krämer I,Engelhardt M,Fichtner S,Neuber B,Medenhoff S,Bertsch U,Hillengass J,Raab MS,Hose D,Ho AD,Goldschmidt H,Hundemer M

    更新日期:2016-02-18 00:00:00

  • A novel immunization strategy using cytokine/chemokines induces new effective systemic immune responses, and frequent complete regressions of human metastatic melanoma.

    abstract::Immune responses have been elicited by a variety of cancer vaccines, but seldom induce regressions of established cancers in humans. As a novel therapeutic immunization strategy, we tested the hypothesis that multiple cytokines/chemokines secreted early in secondary responses ex-vivo might mimic the secretory environm...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1386827

    authors: Valentine FT,Golomb FM,Harris M,Roses DF

    更新日期:2017-10-30 00:00:00

  • HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy.

    abstract::The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enable...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2015.1065369

    authors: Peper JK,Bösmüller HC,Schuster H,Gückel B,Hörzer H,Roehle K,Schäfer R,Wagner P,Rammensee HG,Stevanović S,Fend F,Staebler A

    更新日期:2015-07-01 00:00:00

  • SOX2-specific adaptive immunity and response to immunotherapy in non-small cell lung cancer.

    abstract::Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-small cell lung carcinoma (NSCLC). Preclinical data suggest that pre-existing tumor immunity is important for disease regression upon checkpoint blockade-based ther...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/onci.25205

    authors: Dhodapkar KM,Gettinger SN,Das R,Zebroski H,Dhodapkar MV

    更新日期:2013-07-01 00:00:00

  • Clonal expansion of renal cell carcinoma-infiltrating T lymphocytes.

    abstract::T lymphocytes can mediate the destruction of cancer cells by virtue of their ability to recognize tumor-derived antigenic peptides that are presented on the cell surface in complex with HLA molecules and expand. Thus, the presence of clonally expanded T cells within neoplastic lesions is an indication of ongoing HLA-r...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/onci.26014

    authors: Sittig SP,Køllgaard T,Grønbæk K,Idorn M,Hennenlotter J,Stenzl A,Gouttefangeas C,Thor Straten P

    更新日期:2013-09-01 00:00:00

  • PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates.

    abstract::Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomar...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2020.1786888

    authors: Pico de Coaña Y,Wolodarski M,van der Haar Àvila I,Nakajima T,Rentouli S,Lundqvist A,Masucci G,Hansson J,Kiessling R

    更新日期:2020-08-28 00:00:00

  • Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors.

    abstract::In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the presen...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/21624011.2014.963395

    authors: Devaud C,Westwood JA,Teng MW,John LB,Yong CS,Duong CP,Smyth MJ,Darcy PK,Kershaw MH

    更新日期:2014-12-21 00:00:00

  • Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma.

    abstract::The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune context...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1380765

    authors: Li S,Xu F,Zhang J,Wang L,Zheng Y,Wu X,Wang J,Huang Q,Lai M

    更新日期:2017-10-11 00:00:00

  • Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).

    abstract::TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF-κB activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A2...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1368605

    authors: Azpilikueta A,Bolaños E,Lang V,Labiano S,Aznar MA,Etxeberria I,Teijeira A,Rodriguez-Ruiz ME,Perez-Gracia JL,Jure-Kunkel M,Zapata JM,Rodriguez MS,Melero I

    更新日期:2017-09-21 00:00:00

  • The extent to which melanoma alters tissue-resident dendritic cell function correlates with tumorigenicity.

    abstract::We have shown that melanoma-derived factors alter the function of differentiated tissue-resident dendritic cells (DC) in a tumorigenicity-dependent manner. Soluble factors, including TGFβ1 and VEGF-A, contributed to dendritic cell dysfunction associated with a highly-aggressive melanoma and conferred a phenotype upon ...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2015.1069462

    authors: Hargadon KM

    更新日期:2015-08-12 00:00:00

  • Anti-GD2 antibody 3F8 and barley-derived (1 → 3),(1 → 4)-β-D-glucan: A Phase I study in patients with chemoresistant neuroblastoma.

    abstract::β-glucans are complex, naturally-occurring polysaccharides that prime leukocyte dectin and complement receptor 3. Based on our preclinical findings, indicating that oral barley-derived (1 → 3),(1 → 4)-β-D-glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma, we conducted a Phase I clinica...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/onci.23402

    authors: Modak S,Kushner BH,Kramer K,Vickers A,Cheung IY,Cheung NK

    更新日期:2013-03-01 00:00:00

  • Correlation between previous treatment with BRAF inhibitors and clinical response to pembrolizumab in patients with advanced melanoma.

    abstract::The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain ...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1283462

    authors: Simeone E,Grimaldi AM,Festino L,Giannarelli D,Vanella V,Palla M,Curvietto M,Esposito A,Palmieri G,Mozzillo N,Ascierto PA

    更新日期:2017-01-19 00:00:00

  • Rehmannia glutinosa polysaccharide induces toll-like receptor 4 dependent spleen dendritic cell maturation and anti-cancer immunity.

    abstract::Rehmannia glutinosa polysaccharide (RGP) has shown an activation of immune cells in vitro. However, the immune stimulatory effect of RGP in a mouse in vivo is not well studied. In this study, we examined the effect of RGP on dendritic cell (DC) activation and anticancer immunity in vivo. Treatments of RGP in C56BL/6 m...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1325981

    authors: Xu L,Kwak M,Zhang W,Zeng L,Lee PC,Jin JO

    更新日期:2017-05-12 00:00:00

  • From cell biology to immunology: Controlling metastatic progression of cancer via microRNA regulatory networks.

    abstract::Recently, the study of microRNAs has expanded our knowledge of the fundamental processes of cancer biology and the underlying mechanisms behind tumor metastasis. Extensive research in the fields of microRNA and its novel mechanisms of actions against various cancers has more recently led to the trial of a first cancer...

    journal_title:Oncoimmunology

    pub_type: 杂志文章,评审

    doi:10.1080/2162402X.2016.1230579

    authors: Park JH,Theodoratou E,Calin GA,Shin JI

    更新日期:2016-09-09 00:00:00

  • Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells.

    abstract::Cytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells. They represent an attractive approach for cell-based immunotherapy, as they do not require antigen-specific priming for tumor cell recognition, and can be rapidly expanded in vitro. Their r...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2020.1777046

    authors: Sommaggio R,Cappuzzello E,Dalla Pietà A,Tosi A,Palmerini P,Carpanese D,Nicolè L,Rosato A

    更新日期:2020-06-11 00:00:00

  • NY-ESO-1 expression in sarcomas: A diagnostic marker and immunotherapy target.

    abstract::NY-ESO-1 (CTAG 1B) is highly expressed in the majority of synovial sarcomas and myxoid/round cell liposarcomas as well as in a subset of melanomas, but only rarely in other mesenchymal tumors. This points to a potential for using NY-ESO-1 in the differential diagnosis of these lesions. Furthermore, promising results h...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/onci.21059

    authors: Lai JP,Rosenberg AZ,Miettinen MM,Lee CC

    更新日期:2012-11-01 00:00:00

  • CAR T-cell immunotherapy of MET-expressing malignant mesothelioma.

    abstract::Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1363137

    authors: Thayaparan T,Petrovic RM,Achkova DY,Zabinski T,Davies DM,Klampatsa A,Parente-Pereira AC,Whilding LM,van der Stegen SJ,Woodman N,Sheaff M,Cochran JR,Spicer JF,Maher J

    更新日期:2017-08-14 00:00:00

  • ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism.

    abstract::Immune evasion of tumors poses a major challenge for immunotherapy. For human papillomavirus (HPV)-induced malignancies, multiple immune evasion mechanisms have been described, including altered expression of antigen processing machinery (APM) components. These changes can directly influence epitope presentation and t...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2017.1336594

    authors: Steinbach A,Winter J,Reuschenbach M,Blatnik R,Klevenz A,Bertrand M,Hoppe S,von Knebel Doeberitz M,Grabowska AK,Riemer AB

    更新日期:2017-06-20 00:00:00

  • Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer.

    abstract::Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2018.1486953

    authors: Hagihara K,Chan S,Zhang L,Oh DY,Wei XX,Simko J,Fong L

    更新日期:2018-10-01 00:00:00

  • Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma.

    abstract::Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2018.1434464

    authors: Suryadevara CM,Desai R,Abel ML,Riccione KA,Batich KA,Shen SH,Chongsathidkiet P,Gedeon PC,Elsamadicy AA,Snyder DJ,Herndon JE 2nd,Healy P,Archer GE,Choi BD,Fecci PE,Sampson JH,Sanchez-Perez L

    更新日期:2018-02-21 00:00:00

  • A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition.

    abstract::Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenviro...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2019.1678921

    authors: Bernstock JD,Vicario N,Rong L,Valdes PA,Choi BD,Chen JA,DiToro D,Osorio DS,Kachurak K,Gessler F,Johnston JM Jr,Atkinson TP,Whitley RJ,Bag AK,Gillespie GY,Markert JM,Maric D,Friedman GK

    更新日期:2019-10-21 00:00:00

  • New role of Interleukin-10 in enhancing the antitumor efficacy of oncolytic vaccinia virus for treatment of pancreatic cancer.

    abstract::Although the profile of safety of tumor-targeted oncolytic virus (TOV) is encouraging, the antitumor efficacy of TOV alone is disappointing. Interleukin-10 (IL-10) plays an important role in carcinogenesis and anti-virus immunity. Here we report that tumor-targeted oncolytic vaccinia virus (VV) armed with IL10 shows p...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2015.1038689

    authors: Chard LS,Lemoine NR,Wang Y

    更新日期:2015-07-20 00:00:00

  • Enhanced expression of CD39 and CD73 on T cells in the regulation of anti-tumor immune responses.

    abstract::Synthesis of extracellular adenosine by the ectonucleotidases CD39 and CD73 represents an important pathway of immune suppression in the tumor microenvironment. Using two mouse models (RET transgenic melanoma and Panc02 orthotopic pancreatic adenocarcinoma), we identified an elevated frequency of ectonucleotidase-expr...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.1080/2162402X.2020.1744946

    authors: Shevchenko I,Mathes A,Groth C,Karakhanova S,Müller V,Utikal J,Werner J,Bazhin AV,Umansky V

    更新日期:2020-04-09 00:00:00

  • Functional characterization of a STAT3-dependent dendritic cell-derived CD14+ cell population arising upon IL-10-driven maturation.

    abstract::Interleukin (IL)-10 is a major cancer-related immunosuppressive factor, exhibiting a unique ability to hamper the maturation of dendritic cells (DCs). We have previously reported that IL-10 induces the conversion of activated, migratory CD1a+ DCs found in the human skin to CD14+CD141+ macrophage-like cells. Here, as a...

    journal_title:Oncoimmunology

    pub_type: 杂志文章

    doi:10.4161/onci.23837

    authors: Lindenberg JJ,van de Ven R,Lougheed SM,Zomer A,Santegoets SJ,Griffioen AW,Hooijberg E,van den Eertwegh AJ,Thijssen VL,Scheper RJ,Oosterhoff D,de Gruijl TD

    更新日期:2013-04-01 00:00:00