CD95L mediates tumor counterattack <i>in vitro</i> but induces neutrophil‐independent tumor rejection <i>in vivo</i>

Igney, Frederik H.; Behrens, Christian K.; Krammer, Peter H.

doi:10.1002/ijc.20538

Cited by 30 publications

(21 citation statements)

References 55 publications

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“…The theory is controversial partly because of technical questions about reagents used, such as antibodies and T-cell lines highly sensitive to Fas-mediated apoptosis (14,34). There have been several attempts using in vivo animal models to functionally test the concept; however, the results have been ambiguous (12,17,18,35,36). Frequently, researchers have used tumor cells engineered to overexpress FasL and implanted these, usually s.c., in syngeneic mice.…”

Section: Discussionmentioning

confidence: 99%

Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model

Fingleton

Carter²,

Matrisian³

2007

Cancer Research

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Section: Discussionmentioning

confidence: 99%

Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model

Fingleton

Carter²,

Matrisian³

2007

Cancer Research

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“…Although CD95L-expressing cells efficiently mediate cell death of CD95-sensitive T cells in vitro, the same cells are apparently not protected from rejection in vivo. [10][11][12] As our model is operative under standardized in vitro culture conditions, T cell depletion is independent of environmental influences such as local cytokine pattern, vascularization and accessibility to cellular infiltration. The efficiency of our system might further depend on the fact that CD95L is used in a membrane-bound form.…”

Section: Cd95l Expressed On T Cells Mediates a Dual Functionmentioning

confidence: 99%

“…9 However, transfection of CD95L into murine tumor cells did not enhance tumor growth, but instead induced accelerated tumor rejection by neutrophils in vivo. [10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models.…”

mentioning

confidence: 99%

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

et al. 2006

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Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4 þ and CD8 þ HLA-A1-specifc T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases. Apoptosis mediated by the CD95 system plays a pivotal regulatory role in the maintenance of immune homeostasis. Deficiency in CD95 or CD95L expression in T cells mediates lymphoproliferative disorders due to the lack of apoptosis induction. 1 Paradoxically, several molecules of the CD95 signaling pathway are also required for T cell activation and proliferation. 2 In addition to T cells, live and death of antigenpresenting cells, which initiate T cell responses has to be tightly controlled to avoid the establishment of autoimmunity. 3 Activation-induced cell death (AICD) represents an apoptosis mechanism mediated via the interaction of CD95 with its ligand CD95L, to mediate T cell death and initiate the termination of an immune response to maintain tolerance to self antigens and to prevent autoimmunity. 4 Owing to the constitutive expression of CD95L in immune privileged organs such as testis or eye, 5,6 CD95L was considered as an immunoprotective agent able to counterattack activated T cells in vivo. However, the role of CD95L in transplantation tolerance is still controversial. While allogeneic pancreatic islands transplanted together with syngeneic CD95L expressing myoblasts were tolerated, 7 allogeneic CD95L expressing pancreatic b cells were rejected due to increased neutrophil infiltration. 8 Lack of immunogenicity of tumors and resistance towards T cell attacks were also correlated with the expression of CD95L on tumor tissues. Such tumors were shown to kill CD95-positive cells in vitro. 9 However, transfection of CD95L into murine tumor cells did not enhance tumor growth, but instead induced accelerated tumor rejection by neutrophils in vivo. [10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the hig...

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“…Immunosubversion is a process of active suppression of the immune response by tumor cells. Tumors use numerous different mechanisms ( further referenced as immunoescape mechanisms) of immunosubversion (8,(13)(14)(15)(16), including down-regulation of MHC class I expression (9,10) and up-regulation of expression of CD95L (16), indoleamine-2,3-dioxygenase (14,15), and arginase-1 or transforming growth factor-h and interleukin (IL)-10 (17). Moreover, a significant expansion of regulatory T (T reg ) cells, which are capable of inhibiting both CD4 + and CD8 + T-cell responses, was observed during progression of many types of tumors both in mice and humans (18).…”

Section: Introductionmentioning

confidence: 99%

“…Total RNA was isolated from 5 Â 10 6 cells by using 1 mL of Trizol reagent (Life Technologies-Invitrogen) according to the manufacturer's protocol. RNA (1 Ag) was reverse transcribed using oligo(dT) [12][13][14][15][16][17][18] primer and SuperScript II RNase H À Reverse Transcriptase (Invitrogen). Resulting cDNAs were used for PCR with specific primers for mIL-10 (Genbank accession no.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Immunoescape Mechanisms of BCL1 Leukemia and Induction of CD8+ T-Cell–Mediated BCL1-Specific Resistance in Mice Cured by Targeted Polymer-Bound Doxorubicin

et al. 2008

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BALB/c mice bearing syngeneic BCL1 leukemia, a mouse model of human chronic lymphocytic leukemia, were treated with polymer-bound doxorubicin conjugate targeted with BCL1-specific monoclonal antibody. Such treatment can cure up to 100% of mice and the cured mice show long-lasting resistance to BCL1 leukemia. We show that both CD4 + and CD8 + T cells are required for establishment of the resistance, but only CD8 + T cells are necessary for its maintenance. BCL1 cells express MHC class I and II and also costimulatory molecules CD80 and CD86, which can aid eliciting of antitumor response. On the other hand, BCL1 cells also use several immunoescape mechanisms, such as expression of PD-L1, PD-L2, and interleukin-10. BCL1 cells thus can be recognized by BCL1-specific T cells, but instead of effective priming, such T cells are anergized or deleted by apoptosis. Moreover, BCL1 leukemia progression is accompanied by robust expansion of CD4 + CD25 + Foxp3 + regulatory T (T reg ) cells. Although it has been shown that depletion of T reg cells in tumor-bearing mice can retard tumor growth, direct evidence that expansion of T reg cells can promote tumor growth was lacking. In this study, we provide first direct evidence that expanded T reg cells can indeed promote tumor progression by using mice with selectively expanded T reg cells before inoculation of BCL1 leukemia. Finally, we have also shown that elimination of some immunoescape mechanism (e.g., deletion of T reg ) can significantly improve the therapeutic outcome of chemotherapy. [Cancer Res 2008;68(23):9875-83]

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CD95L mediates tumor counterattack in vitro but induces neutrophil‐independent tumor rejection in vivo

Cited by 30 publications

References 55 publications

Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model

Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

Overcoming Immunoescape Mechanisms of BCL1 Leukemia and Induction of CD8+ T-Cell–Mediated BCL1-Specific Resistance in Mice Cured by Targeted Polymer-Bound Doxorubicin

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