Depletion of Dendritic Cells Delays Ovarian Cancer Progression by Boosting Antitumor Immunity

Huarte, Eduardo; Cubillos-Ruiz, Juan R.; Nesbeth, Yolanda C.; Scarlett, Uciane K.; Martinez, Diana G.; Buckanovich, Ronald J.; Benencia, Fabián; Stan, Radu V.; Keler, Tibor; Sarobe, Pablo; Sentman, Charles L.; Conejo-Garcia, José R.

doi:10.1158/0008-5472.can-08-1167

Cited by 105 publications

(157 citation statements)

References 35 publications

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“…Thus, our recent work about the microenvironment of ovarian cancer, a paradigmatic lethal and frequent form of epithelial cancer, demonstrated that immature CD11c + DEC205 + DCs represent the most frequent leukocyte subset infiltrating solid tumors (2,(8)(9)(10)(11)(12)(13). These DCs home to perivascular locations, where they deliver multiple proangiogenic (2,(8)(9)(10)(11)(12) and immunosuppressive (2,13) mediators. Correspondingly, we recently demonstrated that the elimination of such tumor-associated DCs delays ovarian cancer progression by boosting antitumor immunity (13).…”

Section: Introductionmentioning

confidence: 99%

“…These DCs home to perivascular locations, where they deliver multiple proangiogenic (2,(8)(9)(10)(11)(12) and immunosuppressive (2,13) mediators. Correspondingly, we recently demonstrated that the elimination of such tumor-associated DCs delays ovarian cancer progression by boosting antitumor immunity (13). Thus, it is likely that the release of this crucial immunosuppressive brake enables the awakening of tumor-infiltrating effector lymphocytes, the only known element of the ovarian carcinoma microenvironment capable of exerting spontaneous immune pressure against tumor progression (12,14,15).…”

Section: Introductionmentioning

confidence: 99%

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Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity

Cubillos-Ruiz¹,

Engle²,

Scarlett³

et al. 2009

J. Clin. Invest.

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133

208

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The success of clinically relevant immunotherapies requires reversing tumor-induced immunosuppression.Here we demonstrated that linear polyethylenimine-based (PEI-based) nanoparticles encapsulating siRNA were preferentially and avidly engulfed by regulatory DCs expressing CD11c and programmed cell death 1-ligand 1 (PD-L1) at ovarian cancer locations in mice. PEI-siRNA uptake transformed these DCs from immunosuppressive cells to efficient antigen-presenting cells that activated tumor-reactive lymphocytes and exerted direct tumoricidal activity, both in vivo and in situ. PEI triggered robust and selective TLR5 activation in vitro and elicited the production of hallmark TLR5-inducible cytokines in WT mice, but not in Tlr5 -/-littermates. Thus, PEI is a TLR5 agonist that, to our knowledge, was not previously recognized. In addition, PEI-complexed nontargeting siRNA oligonucleotides stimulated TLR3 and TLR7. The nonspecific activation of multiple TLRs (specifically, TLR5 and TLR7) reversed the tolerogenic phenotype of human and mouse ovarian tumor-associated DCs. In ovarian carcinoma-bearing mice, this induced T cell-mediated tumor regression and prolonged survival in a manner dependent upon myeloid differentiation primary response gene 88 (MyD88; i.e., independent of TLR3). Furthermore, gene-specific siRNA-PEI nanocomplexes that silenced immunosuppressive molecules on mouse tumor-associated DCs elicited discernibly superior antitumor immunity and enhanced therapeutic effects compared with nontargeting siRNA-PEI nanocomplexes. Our results demonstrate that the intrinsic TLR5 and TLR7 stimulation of siRNA-PEI nanoparticles synergizes with the gene-specific silencing activity of siRNA to transform tumor-infiltrating regulatory DCs into DCs capable of promoting therapeutic antitumor immunity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity

Cubillos-Ruiz¹,

Engle²,

Scarlett³

et al. 2009

J. Clin. Invest.

Self Cite

133

208

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“…Although DCs are cells specialized in triggering immune responses, they have been shown to participate in pathological conditions such as cancer and atherosclerosis 4,15,16 . They have been also claimed to participate in angiogenic process 17,18 , even suggested as structurally participating in the developing of new vessels 19,20 . Thus, methods that allow for DC tracking in vivo, and determining their geographical localization in different tissues 4,21,22 are very valuable.…”

Section: Discussionmentioning

confidence: 99%

Generation and Labeling of Murine Bone Marrow-derived Dendritic Cells with Qdot Nanocrystals for Tracking Studies

Muccioli

Pate

Omosebi

et al. 2011

JoVE

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Dendritic cells (DCs) are professional antigen presenting cells (APCs) found in peripheral tissues and in immunological organs such as thymus, bone marrow, spleen, lymph nodes and Peyer's patches [1][2][3] . DCs present in peripheral tissues sample the organism for the presence of antigens, which they take up, process and present in their surface in the context of major histocompatibility molecules (MHC). Then, antigen-loaded DCs migrate to immunological organs where they present the processed antigen to T lymphocytes triggering specific immune responses. One way to evaluate the migratory capabilities of DCs is to label them with fluorescent dyes 4 .Herewith we demonstrate the use of Qdot fluorescent nanocrystals to label murine bone marrow-derived DC. The advantage of this labeling is that Qdot nanocrystals possess stable and long lasting fluorescence that make them ideal for detecting labeled cells in recovered tissues. To accomplish this, first cells will be recovered from murine bone marrows and cultured for 8 days in the presence of granulocyte macrophagecolony stimulating factor in order to induce DC differentiation. These cells will be then labeled with fluorescent Qdots by short in vitro incubation. Stained cells can be visualized with a fluorescent microscopy. Cells can be injected into experimental animals at this point or can be into mature cells upon in vitro incubation with inflammatory stimuli. In our hands, DC maturation did not determine loss of fluorescent signal nor does Qdot staining affect the biological properties of DCs. Upon injection, these cells can be identified in immune organs by fluorescent microscopy following typical dissection and fixation procedures. Video LinkThe video component of this article can be found at https://www.jove.com/video/2785/ Protocol 1. Dissection of mouse femurs and tibiae and culture of bone marrow cells 1. Sacrifice 2 mice by CO 2 asphyxiation and carefully dissect tibias and femurs without cutting the bone ends. 2. Clean the bones from all the attached tissues by using tissue paper. Be careful not to break the bones. 3. Sterilize the bones by immersion in 70% ethanol for 10 min in a 35 mm Petri dish. From this moment, work inside a biosafety hood to avoid contamination of the cell cultures. 4. Recover the bones from the ethanol and let them air dry for 5 min in a Petri dish inside the biosafety cabinet. 5. Cut the femurs in half, and the tibia by its thinnest tip. Infuse the inside of the bone with 1 ml of RPMI medium (without serum but with antibiotics) using a sterile syringe on a sterile Petri dish. 6. The cell suspension is collected and washed 2X in RPMI medium by 10 min centrifugation in a 15 ml centrifuge tube at 1,100 RPM in a refrigerated centrifuge (4°C) with a swinging bucket rotor. 7. After the last wash, resuspend the cells in 2 ml of ACK lysis buffer and incubate for 5 min at room temperature in order to eliminate red blood cells. 8. Add 13 ml of RPMI with 10% FBS, resuspend and wash 2X in this medium with the same settings as describe...

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“…In particular, the presence of DC expressing B7-H1 is associated with poor overall survival (OS) in ovarian cancer, probably by directly inhibiting T cell proliferation and by promoting the induction of FoxP3 + Tregs as well [68][69][70][71]. Thus, the DC population could represent a therapeutic target in ovarian cancer; in this regard, recent murine modeling studies demonstrate improved anti-tumor immunity following specific depletion of DCs [72].…”

Section: Mechanisms Of Immunogenicity and Immunoediting In Ovarian Camentioning

confidence: 99%

Immunotherapy for recurrent ovarian cancer: a further piece of the puzzle or a striking strategy?

Bronte

Cicero

Sortino

et al. 2013

Expert Opinion on Biological Therapy

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Introduction: Treatment of ovarian cancer has been long standardized with the inclusion of surgery and chemotherapy based on platinum and taxanes,\ud this strategy reaching high remission rates. However, when this treatment\ud fails, further options are available with little benefit. Since ovarian cancer\ud has specific immunologic features, actually immunotherapy is under evalua- 15\ud tion to overcome treatment failure in patients experiencing recurrence.\ud Areas covered: Immunogenicity of ovarian cancer and its relationship with\ud clinical outcomes is briefly reviewed. The kinds of immunotherapeutic strategies\ud are summarized. The clinical trials investigating immunotherapy in\ud recurrent ovarian cancer patients are reported. 20\ud Expert opinion: The results of these clinical trials about immunotherapy are\ud interesting, but little clinical benefit has been achieved until now. For this\ud reason, we could conclude that immunotherapy is quite different from other\ud treatment options and it could change the global approach for recurrent\ud ovarian cancer treatment. However, to date only fragmentary findings are 25\ud available to define the real role of immunotherapy in this setting

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Depletion of Dendritic Cells Delays Ovarian Cancer Progression by Boosting Antitumor Immunity

Cited by 105 publications

References 35 publications

Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity

Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity

Generation and Labeling of Murine Bone Marrow-derived Dendritic Cells with Qdot Nanocrystals for Tracking Studies

Immunotherapy for recurrent ovarian cancer: a further piece of the puzzle or a striking strategy?

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