Flt3 ligand lessens the growth of tumors obtained after colon cancer cell injection in rats but does not restore tumor-suppressed dendritic cell function

Favre-Félix, Nathalie; Martin, Monique; Maraskovsky, Eugene; Fromentin, Annie; Moutet, Monique; Solary, Éric; Martin, François; Bonnotte, Bernard

doi:10.1002/(sici)1097-0215(20000615)86:6<827::aid-ijc11>3.0.co;2-r

Cited by 24 publications

(14 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Flt3L alone has been reported to induce the regression of chemically induced sarcomas in mice (45), but this result was not reproduced by others (46,47). Here we show that systemic injections of Flt3L in mice induced a much lower recruitment of DCs to the tumor site compared with intratumoral expression of CCL20.…”

Section: Figurementioning

confidence: 90%

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Furumoto

Soares²,

Engleman³

et al. 2004

J. Clin. Invest.

119

125

View full text Add to dashboard Cite

Nonstandard abbreviations used: antigen (Ag); bone marrow (BM); CG-rich motif (CpG); complete medium (CM); control oligonucleotide (ODN-CTR); effector/target (E/T); Fms-like thyrosine kinase 3 ligand (Flt3L); Langerhans cell (LC); macrophage inflammatory protein-3α (MIP-3α); mean fluorescence intensity (MFI); T cell receptor (TCR). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionThe ability of tumors to escape the immune system has been a major obstacle to the development of effective tumor immunotherapy. Both central and peripheral immune tolerance have been implicated in the failure of tumor-bearing hosts to mount an immune response to their tumors. Central tolerance may play a fundamental role in the lack of response against self-tumor-associated antigens (Ag's), while peripheral tolerance may explain the lack of response against tumor-specific Ag's. DCs are believed to play a critical role in antitumor immune responses. These cells are the most potent APCs known, uniquely capable of inducing immunity to newly introduced Ag's (1, 2). Normally, DCs reside as immature cells in peripheral tissues where they sample the environment by taking up and processing local Ag's. In the presence of certain toll-like receptor ligands, these cells not only take up and process Ag's but also undergo activation and maturation and then migrate to the draining LNs where they prime specific CD4 and CD8 T cells to these Ag's. The presence in a wide range of tumors of immature DCs that are unable to stimulate T cells (3-9) suggests a possible role for these cells in the failure of tumor-bearing hosts to mount an effective antitumor response. This view is supported by a recent study in melanoma patients that showed that tumor-associated DCs are present mostly at the periphery of tumors and express low levels of costimulatory molecules, while the majority of T cells infiltrating tumors have a naive phenotype (10). The presence of naive but not memory or effector T cells in tumors may be related to the failure of tumoral DCs to provide an adequate stimulus or possibly to the induction of T cell tolerance by the immature DCs. By contrast to tumoral DCs, in vitro-generated DCs can induce an effective T cell-mediated antitumor immune response in vivo (11), indicating that the T cells of tumor-bearing hosts are capable of recognizing and responding to tumor Ag's and suggesting again that the tumor milieu prevents tumoral DCs from inducing an effective immune response. Indeed, injection of immature Ag-pulsed DCs can induce a specific tolerogenic response, while similarly pulsed DCs, when matured, induced a typical Th1 immune response (12).Based on the recognition of the central role of DCs in initiating immune responses, a variety of strategies have been devised to use DCs to stimulate immunity against tumor Ag's. Most of these strategies rely on the activation and maturation of DCs ex vivo and their subsequent reinfusion to tumor-bearing recipients after a pulse with tumor Ag's expressed as...

show abstract

Section: Figurementioning

confidence: 90%

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Furumoto

Soares²,

Engleman³

et al. 2004

J. Clin. Invest.

119

125

View full text Add to dashboard Cite

show abstract

“…30 Studies have also shown that FL stimulation may have an anti-leukemic effect, and that the effect requires NK cells. 40 In addition, a number of studies have appeared on the use of FL for decreasing growth of colon tumor and melanomas, 41,42 and for enhancing the immunogenicity of infectious disease vaccines such as HIV-1, polyomavirus and herpes simplex virus 1. 43,44 Tel-FLT3 mice could provide a valuable tool for in vivo expanded DCs and NK cells for antitumor studies.…”

Section: Activated Flt3 Expression Increases the Stem Cell/ Progenitomentioning

confidence: 99%

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

et al. 2007

Leukemia

View full text Add to dashboard Cite

Evidence is continuing to accumulate that the FMS-like tyrosine kinase 3 (FLT3) receptor plays an important role in acute leukemias. Acute myeloid leukemia patients often express constitutive active mutant forms of the receptor in their leukemic cells. A t(12;13)(p13;q12) translocation between Tel and the FLT3 receptor was recently described in a patient with myeloproliferative disease (MPD). Here a Tel-FLT3 construct mimicking this fusion protein was used to generate transgenic mice. The fusion protein was previously found to constitutively activate FLT3 signaling and transform Ba/F3 cells. Expression of the fusion protein in the transgenic mice was found in all tissues assayed including spleen, bone marrow (BM), thymus and liver. These mice developed splenomegaly and had a high incidence of MPD with extramedullary hematopoiesis in the liver and lymph nodes. Spleens also had increased dendritic and natural killer cell populations. In vitro analysis of the hematopoietic progenitor cells derived from Tel-FLT3 transgenic mice showed a significant increase in the number of CFU-GM in the BM, and CFU-GM, BFU-E and CFU-GEMM in the spleen. BM also showed significant increases of in vivo CFU-S colonies. Thus, transgenic mice expressing constitutively activated Tel-FLT3 develop MPD with a long latency and also result in the expansion of the hematopoietic stem/progenitor cells.

show abstract

“…The tumorigenic and tolerogenic PRO model has proved to be a useful model to study the role of cancer cells death in the development of an antitumor response (30,31). When injected in syngeneic rats, these cells give progressive, lethal tumors that do not immunize the host against an additional challenge (32).…”

Section: Depletion Of Cytochrome C Inhibits Pro Cell Tumorigenicity Imentioning

confidence: 99%

Increased Immunogenicity of Colon Cancer Cells by Selective Depletion of Cytochromec

et al. 2004

Self Cite

View full text Add to dashboard Cite

We and others have previously reported in an in vivo rat colon cancer cell model that cell death precedes and is necessary for the development of a specific antitumoral immune response. To sensitize colon cancer cells to death, we depleted cytochrome c by stable transfection with an antisense construct. Cytochrome c depletion sensitizes human and rat colon cancer cells to a nonapoptotic, nonautophagic death induced by various stimuli. This increased sensitization to a necrosis-like cell death may be related to a decrease in cellular ATP levels and an increase in reactive oxygen species production caused by cytochrome c depletion. In vivo, depletion of cytochrome c decreases the tumorigenicity of colon cancer cells in syngeneic rats without influencing their growth in immune-deficient animals. Furthermore, decreased expression of cytochrome c in tumor cells facilitates in vivo "necrotic" cell death and the induction of a specific immune response. These results delineate a novel strategy to sensitize colon cancer cells to chemotherapy and to increase their immunogenicity in immunocompetent hosts.

show abstract

Flt3 ligand lessens the growth of tumors obtained after colon cancer cell injection in rats but does not restore tumor-suppressed dendritic cell function

Cited by 24 publications

References 20 publications

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Increased Immunogenicity of Colon Cancer Cells by Selective Depletion of Cytochromec

Contact Info

Product

Resources

About