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1.
Gene Ther ; 21(4): 393-401, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24572789

ABSTRACT

A number of antitumor vaccines have recently shown promise in upregulating immune responses against tumor antigens and improving patient survival. In this study, we examine the effectiveness of vaccination using interleukin (IL)-15-expressing tumor cells and also examine their ability to upregulate immune responses to tumor antigens. We demonstrated that the coexpression of IL-15 with its receptor, IL-15Rα, increased the cell-surface expression and secretion of IL-15. We show that a gene transfer approach using recombinant adenovirus to express IL-15 and IL-15Rα in murine TRAMP-C2 prostate or TS/A breast tumors induced antitumor immune responses. From this, we developed a vaccine platform, consisting of TRAMP-C2 prostate cancer cells or TS/A breast cancer cells coexpressing IL-15 and IL-15Rα that inhibited tumor formation when mice were challenged with tumor. Inhibition of tumor growth led to improved survival when compared with animals receiving cells expressing IL-15 alone or unmodified tumor cells. Animals vaccinated with tumor cells coexpressing IL-15 and IL-15Rα showed greater tumor infiltration with CD8(+) T and natural killer (NK) cells, as well as increased antitumor CD8(+) T-cell responses. Vaccination with IL-15/IL-15Rα-modified TS/A breast cancer cells provided a survival advantage to mice challenged with unrelated murine TUBO breast cancer cells, indicating the potential for allogeneic IL-15/IL-15Rα-expressing vaccines.


Subject(s)
Breast Neoplasms/genetics , Interleukin-15 Receptor alpha Subunit/biosynthesis , Interleukin-15/biosynthesis , Prostatic Neoplasms/genetics , Animals , Breast Neoplasms/pathology , Breast Neoplasms/therapy , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor/metabolism , Cell Line, Tumor/transplantation , Cell- and Tissue-Based Therapy , Dendritic Cells , Disease Models, Animal , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Vaccination
2.
Clin Exp Immunol ; 157(1): 9-19, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19659765

ABSTRACT

The generation and maintenance of immune responses are controlled by both co-stimulatory and co-inhibitory signalling through T cell co-receptors, many of which belong to the immunoglobulin-like superfamily or the tumour necrosis factor receptor superfamily. Agonistic or antagonistic monoclonal antibodies targeting these co-receptors have the potential to enhance immunity. Furthermore, their activity on the immunosuppressive regulatory T cell populations which are prevalent within many tumours provides an additional rationale for their use as anti-cancer therapies. This review summarizes the interactions between cancer and the immune system, highlighting the ways in which these new classes of immunostimulatory antibodies might enhance anti-tumour immunity and summarizing early clinical experience with their use.


Subject(s)
Immunotherapy/methods , Neoplasms/therapy , Animals , Antibodies, Monoclonal/therapeutic use , Antigens, CD/immunology , CTLA-4 Antigen , Humans , Immunoglobulins/immunology , Lymphocyte Activation , Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Tumor Necrosis Factor-alpha/immunology
3.
J Exp Med ; 194(6): 823-32, 2001 Sep 17.
Article in English | MEDLINE | ID: mdl-11560997

ABSTRACT

Therapeutic efficacy of a tumor cell-based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte-associated antigen (CTLA)-4 pathway or the CD25(+) regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25(+) Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2(180-188)-specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8(+) T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.


Subject(s)
Antigens, Differentiation/immunology , CD4-Positive T-Lymphocytes/immunology , Immunoconjugates , Melanoma, Experimental/immunology , Receptors, Interleukin-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Abatacept , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antigens, CD , Antigens, Neoplasm/immunology , Biomarkers , CTLA-4 Antigen , Female , Immunotherapy , Intramolecular Oxidoreductases/immunology , Lymphocyte Depletion , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Nude , Tumor Cells, Cultured
4.
J Exp Med ; 194(4): 481-9, 2001 Aug 20.
Article in English | MEDLINE | ID: mdl-11514604

ABSTRACT

We have previously shown that small B16 melanomas can be successfully treated using a combination of anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibody with a granulocyte/macrophage colony-stimulating factor (GM-CSF) producing irradiated tumor cell vaccine. Regression of tumors results in long-lasting immunity and is frequently accompanied by autoimmune depigmentation. Here we examine the cellular and molecular mechanisms of this combined treatment. Histological examination of depigmented lesions revealed infiltration of polymorphonuclear cells and deposition of antibody. The combination therapy also induced tumor rejection and skin depigmentation in B cell-deficient and in CD4(+) T cell-depleted mice. Both effects of the treatment absolutely required CD8(+) T cells. Analysis of the response in successfully treated mice revealed elevated levels of CD8(+) T cells specific for a nonameric peptide consisting of residues 180-188 of the melanocyte differentiation antigen tyrosinase-related protein (TRP)2. There was no evidence of reactivity to the melanocyte antigens gp100, tyrosinase, Mart1/MelanA, or TRP1. Fas-FasL interactions and perforin played a role in mounting the effector response, whereas the tumor necrosis factor pathway was not required. The cellular requirements for tumor rejection in this therapeutic setting were strikingly different from those in a prophylactic setting. In particular, if mice received a prophylactic vaccine consisting of anti-CTLA-4 and B16-GM-CSF before tumor challenge, full protection was obtained even in the absence of CD8(+) T cells. Our data demonstrate that therapeutic autoreactive CD8(+) T cell responses can effectively be generated in tumor-bearing mice and stresses the value of studying tumor immunity in a therapeutic rather than a prophylactic setting.


Subject(s)
Antigens, Differentiation/immunology , Cancer Vaccines/immunology , Immunoconjugates , Melanoma, Experimental/therapy , Abatacept , Animals , Antigens, CD , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , CTLA-4 Antigen , Cancer Vaccines/therapeutic use , Female , Melanoma, Experimental/immunology , Mice , Mice, Inbred C57BL
5.
Nature ; 409(6816): 97-101, 2001 Jan 04.
Article in English | MEDLINE | ID: mdl-11343121

ABSTRACT

T-lymphocyte activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-cell immune responses. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals. To understand the role of ICOS in T-cell activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-cell activation and proliferation are defective in the absence of ICOS. In addition, ICOS -/- T cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/physiology , Lymphocyte Activation , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , Antibody Formation , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Cell Differentiation , Cells, Cultured , Encephalomyelitis, Autoimmune, Experimental/immunology , Gene Targeting , Hemocyanins/immunology , Inducible T-Cell Co-Stimulator Protein , Interleukin-13/biosynthesis , Interleukin-4/biosynthesis , Lymph Nodes/pathology , Mice , Mice, Knockout , Molecular Sequence Data , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , T-Lymphocytes/cytology
6.
Annu Rev Immunol ; 19: 565-94, 2001.
Article in English | MEDLINE | ID: mdl-11244047

ABSTRACT

The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.


Subject(s)
Antigens, Differentiation/immunology , Immunoconjugates , Immunotherapy , Neoplasms/therapy , T-Lymphocyte Subsets/immunology , Abatacept , Adenocarcinoma/immunology , Adenocarcinoma/therapy , Amino Acid Motifs , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antigens, CD , Antigens, Differentiation/genetics , CD28 Antigens/immunology , CTLA-4 Antigen , Cell Cycle/physiology , Cell Differentiation , Clonal Anergy , Cytokines/physiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Humans , Immune Tolerance/immunology , Lymphocyte Activation , Lymphoproliferative Disorders/genetics , Macromolecular Substances , Male , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy , Mice , Mice, Knockout , Models, Immunological , Neoplasms/immunology , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology
7.
Proc Natl Acad Sci U S A ; 98(5): 2587-92, 2001 Feb 27.
Article in English | MEDLINE | ID: mdl-11226283

ABSTRACT

Similarities in the phenotypes of mice deficient for cytotoxic T lymphocyte antigen-4 (CTLA-4) or transforming growth factor-beta1 (TGF-beta1) and other observations have led to speculation that CTLA-4 mediates its inhibitory effect on T cell activation via costimulation of TGF-beta production. Here, we examine the role of TGF-beta in CTLA-4-mediated inhibition of T cell activation and of CTLA-4 in the regulation of TGF-beta production. Activation of AND TCR transgenic mouse T cells with costimulatory receptor-specific antigen presenting cells results in efficient costimulation of proliferation by CD28 ligation and inhibition by CTLA-4 ligation. Neutralizing antibody to TGF-beta does not reverse CTLA-4-mediated inhibition. Also, CTLA-4 ligation equally inhibits proliferation of wild-type, TGF-beta1(-/-), and Smad3(-/-) T cells. Further, CTLA-4 engagement does not result in the increased production of either latent or active TGF-beta by CD4(+) T cells. These results indicate that CTLA-4 ligation does not regulate TGF-beta production and that CTLA-4-mediated inhibition can occur independently of TGF-beta. Collectively, these data demonstrate that CTLA-4 and TGF-beta represent distinct mechanisms for regulation of T cell responses.


Subject(s)
Antigens, Differentiation/physiology , CD4-Positive T-Lymphocytes/physiology , Immunoconjugates , Lymphocyte Activation/physiology , Transforming Growth Factor beta/physiology , Abatacept , Animals , Antigen-Presenting Cells/immunology , Antigens, CD , CTLA-4 Antigen , Cell Division , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neutralization Tests , Transforming Growth Factor beta/immunology
8.
Proc Natl Acad Sci U S A ; 97(23): 12711-6, 2000 Nov 07.
Article in English | MEDLINE | ID: mdl-11050166

ABSTRACT

We examined how cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates heterogeneous CD4(+) T cell responses by using experimental autoimmune encephalomyelitis (EAE), a CD4(+) T cell-mediated disease that is subject to regulation by CTLA-4. Disease incidence and severity were used as measures of in vivo CD4(+) T cell responses. The frequency, cytokine production, and reactivity of primed T cells were determined from animals immunized with proteolipid protein (PLP)-139-151 (disease agonist), PLP-Q (disease antagonist), or both peptides, and treated with control or anti-CTLA-4 antibody to analyze the responding population. CTLA-4 blockade exacerbated disease in PLP-139-151-primed animals and overcame disease antagonism in coimmunized animals, but did not permit disease induction in PLP-Q-primed animals. Experimental autoimmune encephalomyelitis enhancement was associated with increased frequencies of cytokine-producing cells and increased ratios of IFN-gamma to IL-4 secretors responsive to PLP-139-151. Priming with PLP-Q elicited IL-4 and IL-2, but not IFN-gamma secretors cross-reactive with PLP-139-151. Strikingly, CTLA-4 blockade was found to decrease rather than increase the frequencies of cross-reactive IL-4 and IL-2 secretors. Thus, CTLA-4 engagement limits the size, but increases the breadth, of reactivity of a primed pool of CD4(+) T cells, consequently regulating its function.


Subject(s)
Antigens, Differentiation/immunology , CD4-Positive T-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunoconjugates , T-Lymphocytes, Cytotoxic/immunology , Abatacept , Animals , Antigens, CD , CD4-Positive T-Lymphocytes/pathology , CTLA-4 Antigen , Cell Size , Cricetinae , Cross Reactions , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Female , Interferon-gamma/metabolism , Interleukin-4/metabolism , Mice , Myelin Proteolipid Protein/immunology , Myelin Proteolipid Protein/pharmacology , Peptide Fragments/immunology , Peptide Fragments/pharmacology , Th1 Cells/immunology
9.
Proc Natl Acad Sci U S A ; 97(22): 12204-9, 2000 Oct 24.
Article in English | MEDLINE | ID: mdl-11035773

ABSTRACT

Engagement of the T cell costimulatory receptor CTLA-4 can potently down-regulate an immune response. For example, in a T cell receptor transgenic mouse model of autoimmune diabetes, CTLA-4 interactions keep pancreatic islet-reactive T cells in check, evidenced by the finding that mAb blockade of CTLA-4 rapidly provokes diabetes in animals that would not normally succumb until many months later. Interestingly, this effect is only observed early in the course of disease, before insulitis is stably entrenched. Here, we have exploited a highly synchronous and easily manipulable transfer system to determine precisely when CTLA-4 must be engaged to check the diabetogenicity of islet-reactive T cells. Our results indicate that CTLA-4 interactions during initial priming of the T cells in the pancreatic lymph nodes are not determinant. Rather, the critical interactions occur when the T cells secondarily reencounter their antigen in the target organ, the pancreatic islets. In addition, we made use of CTLA-4-deficient mice to bolster our interpretation that CTLA-4 engagement has a dampening rather than an enhancing influence on diabetes progression.


Subject(s)
Antigens, Differentiation/immunology , Diabetes Mellitus, Type 1/immunology , Immunoconjugates , T-Lymphocytes/immunology , Abatacept , Animals , Antibodies, Monoclonal/immunology , Antigens, CD , CTLA-4 Antigen , Disease Models, Animal , Lymph Nodes/immunology , Mice , Mice, Transgenic , Pancreas/immunology
10.
Cancer Res ; 60(9): 2444-8, 2000 May 01.
Article in English | MEDLINE | ID: mdl-10811122

ABSTRACT

We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.


Subject(s)
Adenocarcinoma/therapy , Antigens, Differentiation/immunology , Cancer Vaccines/therapeutic use , Immunization, Passive , Immunoconjugates , Prostatic Neoplasms/therapy , Abatacept , Animals , Antibodies, Neoplasm/pharmacology , Antigens, CD , CTLA-4 Antigen , Cancer Vaccines/radiation effects , Immunohistochemistry , Inflammation , Male , Mice , Mice, Transgenic , Prostatic Neoplasms/immunology
11.
J Autoimmun ; 14(2): 123-31, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10677243

ABSTRACT

Recent studies demonstrated that engagement of cytotoxic T lymphocyte antigen 4 (CTLA-4)/(CD152) generates an inhibitory signal to T cells which arrests an on-going immune response. Since aberrant CD152 activity is thought to contribute to autoimmunity, we examined the effect of CD152-mediated inhibitory signals on the response to self and foreign antigens in autoimmune, diabetes-prone NOD and non-autoimmune BALB/c mice. The interaction of CD152 with its ligand B7 was prevented by treating the mice with anti-CD152 blocking antibody, before and following immunization of the mice with the self-antigen, syngeneic islet cells, or the foreign antigen, key-hole limpet hemocyanin (KLH). CD152 blockade in BALB/c mice stimulated a robust islet-specific T cell-mediated immune response compared to control antibody-treated mice. The augmentation of T cell responses in BALB/c mice was consistent with the role proposed for CD152 as a down-regulator of T cell activation responses. Furthermore, CD152 blockade unmasked islet cell specific autoreactive T cells in the non-autoimmune BALB/c mouse. Conversely, CD152 blockade in NOD mice failed to regulate islet-specific auto-reactive T cell responses. However, CD152 blockade enhanced the T cell response to the exogenous, foreign antigen KLH in both non-autoimmune BALB/c and autoimmune NOD mice. Collectively, these results suggest that there is not a global defect in CD152-mediated regulation of peripheral T cell immune responses in NOD autoimmune mice but rather, a defect specific to T cells recognizing self antigen.


Subject(s)
Antigens, Differentiation/immunology , Autoimmunity , Immunoconjugates , T-Lymphocytes/immunology , Abatacept , Animals , Antibodies/pharmacology , Antigens, CD , Autoantigens , CTLA-4 Antigen , Diabetes Mellitus, Type 1/immunology , Hemocyanins/immunology , Interferon-gamma/biosynthesis , Islets of Langerhans/immunology , Lymphocyte Activation , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Receptors, Interleukin-2/metabolism
12.
J Immunol ; 164(7): 3543-53, 2000 Apr 01.
Article in English | MEDLINE | ID: mdl-10725709

ABSTRACT

The effect of B7-mediated costimulation on T cell homeostasis was examined in studies of B7-1 (CD80) and B7-2 (CD86) transgenic as well as B7-deficient mice. B7 overexpression in transgenic mice resulted in marked polyclonal peripheral T cell hyperplasia accompanied by skewing toward an increased proportion of CD8 single-positive cells and a decreased proportion of CD4 single-positive cells in thymus and more markedly in peripheral T cells. B7-induced T cell expansion was dependent on both CD28 and TCR expression. Transgenic overexpression of B7-1 or B7-2 resulted in down-regulation of cell surface CD28 on thymocytes and peripheral T cells through a mechanism mediated by intercellular interaction. Mice deficient in B7-1 and B7-2 exhibited changes that were the reciprocal of those observed in B7-overexpressing transgenics: a marked increase in the CD4/CD8 ratio in peripheral T cells and an increase in cell surface CD28 in thymus and peripheral T cells. These reciprocal effects of genetically engineered increase or decrease in B7 expression indicate that B7 costimulation plays a physiological role in the regulation of CD4+ and CD8+ T cell homeostasis.


Subject(s)
Antigens, CD/physiology , B7-1 Antigen/physiology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Homeostasis/immunology , Immunoconjugates , Membrane Glycoproteins/physiology , Abatacept , Animals , Antigens, CD/biosynthesis , Antigens, CD/genetics , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/genetics , B7-1 Antigen/biosynthesis , B7-1 Antigen/genetics , B7-2 Antigen , CD28 Antigens/biosynthesis , CD28 Antigens/genetics , CD28 Antigens/physiology , CD4-CD8 Ratio , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen , Down-Regulation/genetics , Down-Regulation/immunology , Homeostasis/genetics , Hyperplasia , Lymphocyte Activation/genetics , Lymphoid Tissue/immunology , Lymphoid Tissue/metabolism , Lymphoid Tissue/pathology , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/genetics , Mice , Mice, Congenic , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Transgenic , Phenotype , Receptors, Antigen, T-Cell/biosynthesis , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell, alpha-beta/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/genetics , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
13.
Proc Natl Acad Sci U S A ; 96(26): 15074-9, 1999 Dec 21.
Article in English | MEDLINE | ID: mdl-10611340

ABSTRACT

Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection. For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%. Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive C2 lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.


Subject(s)
Antibodies/therapeutic use , Antigens, Differentiation/immunology , Immunoconjugates , Immunotherapy/methods , Prostatic Neoplasms/therapy , Abatacept , Animals , Antigens, CD , CTLA-4 Antigen , Chemotherapy, Adjuvant/methods , Lymphatic Metastasis/prevention & control , Male , Mice , Mice, Inbred C57BL , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery
14.
Proc Natl Acad Sci U S A ; 96(20): 11476-81, 1999 Sep 28.
Article in English | MEDLINE | ID: mdl-10500201

ABSTRACT

The efficacy of therapeutic vaccination for the treatment of cancer is limited by peripheral tolerance to tumor antigens. In vivo blockade of CTLA-4, a negative regulator of T cell function, can induce the regression of established tumors and can augment the tumor rejection achieved through therapeutic vaccination. These outcomes may reflect enhanced tumor-specific T cell priming and/or interference with the development of tolerance to tumor antigens. We examined the effect of CTLA-4 blockade on the fate and function of T cells specific for a model tumor antigen in the tumor-bearing host. We found that while CTLA-4 blockade enhanced the priming of responsive T cells, it did not prevent the induction of tolerance to tumor antigens. These results demonstrate that there is a critical window in which the combination of CTLA-4 blockade and vaccination achieves an optimal response, and they point to mechanisms other than CTLA-4 engagement in mediating peripheral T cell tolerance to tumor antigens.


Subject(s)
Antigens, Differentiation/physiology , Antigens, Neoplasm/immunology , Immune Tolerance , Immunoconjugates , T-Lymphocytes/immunology , Abatacept , Animals , Antigens, CD/physiology , B7-1 Antigen/physiology , B7-2 Antigen , CTLA-4 Antigen , Male , Membrane Glycoproteins/physiology , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/immunology , Vaccination
15.
J Exp Med ; 190(3): 355-66, 1999 Aug 02.
Article in English | MEDLINE | ID: mdl-10430624

ABSTRACT

We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.


Subject(s)
Antigens, Differentiation/biosynthesis , Antineoplastic Combined Chemotherapy Protocols/immunology , Autoimmune Diseases/immunology , Cancer Vaccines/immunology , Graft Rejection/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Immunoconjugates , Melanoma, Experimental/immunology , T-Lymphocytes, Cytotoxic/immunology , Vitiligo/immunology , Abatacept , Adjuvants, Immunologic/therapeutic use , Animals , Antibodies, Monoclonal/therapeutic use , Antigens/immunology , Antigens, CD , Antigens, Differentiation/immunology , Antigens, Ly , Antigens, Surface , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Autoimmune Diseases/therapy , CD8-Positive T-Lymphocytes/immunology , CTLA-4 Antigen , Cancer Vaccines/therapeutic use , Cell Survival/immunology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Hair Color/immunology , Immunosuppressive Agents/therapeutic use , Injections, Subcutaneous , Lectins, C-Type , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Lymphocyte Activation , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , NK Cell Lectin-Like Receptor Subfamily B , Neoplasm Transplantation , Proteins/immunology , Skin Pigmentation/immunology , Vitiligo/pathology , Vitiligo/therapy
16.
Proc Natl Acad Sci U S A ; 96(15): 8603-8, 1999 Jul 20.
Article in English | MEDLINE | ID: mdl-10411922

ABSTRACT

CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, characterized by polyclonal expansion of peripheral lymphocytes. To examine the effect of restricting the CD4(+) TCR repertoire on the phenotype of CTLA-4-deficient mice and to assess the influence of CTLA-4 on peptide-specific CD4(+) T cell responses in vitro, an MHC class II-restricted T cell receptor (AND TCR) transgene was introduced into the CTLA-4(-/-) animals. The expression of the AND TCR transgene by CD4(+) T cells delays but does not prevent the lymphoproliferation in the CTLA-4(-/-) mice. The CD4(+) T cells become preferentially activated and expand. Interestingly, young AND TCR(+) CTLA-4(-/-) mice carrying a null mutation in the rag-1 gene remain healthy and the T cells maintain a naive phenotype until later in life. We demonstrate that CTLA-4 regulates the peptide-specific proliferative response generated by naive and previously activated AND TCR(+) RAG(-/-) T cells in vitro. The absence of CTLA-4 also augments the responder frequency of cytokine-secreting AND TCR(+) RAG(-/-) T cells. These results demonstrate that CTLA-4 is a key regulator of peptide-specific CD4(+) T cell responses and support the model that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4(+) vs. CD8(+) T cells.


Subject(s)
Antigens, Differentiation/immunology , CD4-Positive T-Lymphocytes/immunology , Immunoconjugates , Abatacept , Animals , Antigens, CD , CD8-Positive T-Lymphocytes/immunology , CTLA-4 Antigen , Cell Count , Flow Cytometry , Histocompatibility Antigens Class II/immunology , Homeodomain Proteins/genetics , Homeodomain Proteins/immunology , Mice , Mice, Knockout , Peptides/immunology , Phenotype , Receptors, Antigen, T-Cell/immunology
17.
J Immunol ; 162(10): 5813-20, 1999 May 15.
Article in English | MEDLINE | ID: mdl-10229815

ABSTRACT

CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.


Subject(s)
Antigens, Differentiation/metabolism , CD4-Positive T-Lymphocytes/immunology , Immunoconjugates , Immunosuppressive Agents/metabolism , Lymphocyte Activation , Nuclear Proteins , Proto-Oncogene Proteins , Tumor Suppressor Proteins , Abatacept , Animals , Antigens, CD , Biological Transport , CD28 Antigens/metabolism , CD3 Complex/metabolism , CTLA-4 Antigen , Cell Cycle , Cell Cycle Proteins/metabolism , Cyclin D3 , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinases/metabolism , Cyclins , DNA-Binding Proteins/metabolism , Genes, Reporter , Humans , Interleukin-2/biosynthesis , Mice , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , NFATC Transcription Factors , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/isolation & purification , S-Phase Kinase-Associated Proteins , Transcription Factors/metabolism , Transcription, Genetic
18.
Curr Opin Cell Biol ; 11(2): 203-10, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10209159

ABSTRACT

During the past several years, the critical role of costimulatory molecules in regulating T cell responses has been demonstrated. Costimulatory molecule CD28 enhances whereas CTLA-4 downmodulates T cell responses. An understanding of the integration of the signals mediated by costimulatory molecules and the T cell receptor at the cellular and molecular levels is just beginning to be achieved.


Subject(s)
Antigens, Differentiation/immunology , CD28 Antigens/immunology , Immunoconjugates , Lymphocyte Activation , Receptors, Antigen, T-Cell/immunology , Signal Transduction/physiology , T-Lymphocytes/immunology , Abatacept , Animals , Antigen Presentation , Antigens, CD/immunology , B7-1 Antigen/immunology , B7-2 Antigen , CTLA-4 Antigen , Humans , Lymphokines/metabolism , Membrane Glycoproteins/immunology , Mice , Models, Immunological , Receptor-CD3 Complex, Antigen, T-Cell/immunology , T-Lymphocytes/metabolism
20.
Eur J Immunol ; 28(10): 3137-43, 1998 10.
Article in English | MEDLINE | ID: mdl-9808182

ABSTRACT

Negative as well as positive co-stimulation appears to play an important role in controlling T cell activation. CTLA-4 has been proposed to negatively regulate T cell responses. CTLA-4-deficient mice develop a lymphoproliferative disorder, initiated by the activation and expansion of CD4+ T cells. To assess the function of CTLA-4 on CD8+ T cells, CTLA-4(-/-) animals were crossed to an MHC class I-restricted 2C TCR transgenic mouse line. We demonstrate that although the primary T cell responses were similar, the CTLA-4-deficient 2C TCR+ CD8+ T cells displayed a greater proliferative response upon secondary stimulation than the 2C TCR+ CD8+ T cells from CTLA-4 wild-type mice. These results suggest that CTLA-4 regulates antigen-specific memory CD8+ T cell responses.


Subject(s)
Antigens, Differentiation/immunology , CD8-Positive T-Lymphocytes/immunology , Immunoconjugates , Abatacept , Animals , Antigens, CD , CTLA-4 Antigen , Cell Division , Cells, Cultured , Female , Immunophenotyping , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peptides
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