CTLA-4 blockade synergizes with tumor-derived granulocyte– macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma

Hurwitz, Arthur A.; Yu, Tina F.-Y.; Leach, Dana R.; Allison, James P.

doi:10.1073/pnas.95.17.10067

Cited by 343 publications

(200 citation statements)

References 30 publications

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“…There are considerable data to support a role for CTLA-4 in the down-regulation of immune responses, and a number of strategies to restore or enhance in vivo immune responses by inhibiting CTLA-4 signal transduction have been proposed (61,62). However, our findings indicate that T cell anergy can be established in the absence of CTLA-4 function, and that studies to establish or reverse Ag-specific anergy should not focus exclusively on CTLA-4.…”

Section: Discussioncontrasting

confidence: 48%

Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction

Frauwirth

Alegre

Thompson

2000

The Journal of Immunology

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Immunologic tolerance in T lymphocytes is maintained through both thymic and peripheral contributions. One peripheral tolerance mechanism is the induction of T cell anergy, a form of nonresponsiveness resulting from incomplete T cell activation, such as stimulation through the TCR in the absence of costimulation. Recent reports have suggested that engagement of the inhibitory receptor CTLA-4 by its B7 ligand is critical for the initiation of anergy. We tested the importance of CTLA-4 in anergy induction in primary T cells with an in vitro anergy system. Using both CTLA-4/B7-blocking agents and CTLA-4-deficient T cells, we found that T cell anergy can be established in the absence of CTLA-4 expression and/or function. Even in the absence of CTLA-4 signal transduction, T cells activated solely through TCR ligation lose the ability to proliferate as a result of autocrine IL-2 production upon subsequent receptor engagement. Thus, CTLA-4 signaling is not required for the development of T cell anergy.

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Section: Discussioncontrasting

confidence: 48%

Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction

Frauwirth

Alegre

Thompson

2000

The Journal of Immunology

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“…For example, modulation of the immune response to tumor Ag-targeted vaccination, through the elimination of regulatory T cells (Treg) 5 (1) or the provision of additional T cell costimulation (2), is necessary to achieve therapeutic outcomes in mouse models of tumor tolerance. This concept is supported by early studies testing CTLA-4-blocking Abs in combination with Ag-targeted vaccination (3,4).…”

Section: Ox40 Costimulation Synergizes With Gm-csf Whole-cell Vaccinamentioning

confidence: 59%

OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

Murata

Ladle

Kim

et al. 2006

The Journal of Immunology

100

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T cell costimulation via OX40 is known to increase CD4+ T cell expansion and effector function and enhances the development of T cell memory. OX40 costimulation can also prevent, and even reverse, CD4+ T cell anergy. However, the role of OX40 in CD8+ T cell function is less well defined, particularly in the setting of immune tolerance. To determine the effects of OX40 costimulation on the induction of the host CD8+ T cell repertoire to an endogenous tumor Ag, we examined the fate of CD8+ T cells specific for the immunodominant rat HER-2/neu epitope, RNEU420–429, in FVB MMTV-neu (neu-N) mice, which express rat HER-2/neu protein in a predominantly mammary-restricted fashion. We show that the RNEU420–429-specific T cell repertoire in neu-N mice expands transiently after vaccination with a neu-targeted GM-CSF-secreting whole-cell vaccine, but quickly declines to an undetectable level. However, OX40 costimulation, when combined with GM-CSF-secreting tumor-targeted vaccination, can break established CD8+ T cell tolerance in vivo by enhancing the expansion, and prolonging the survival and effector function of CD8+ T cells specific for RNEU420–429. Moreover, we demonstrate that OX40 expression is up-regulated on both CD4+ and CD8+ T cells shortly after administration of a GM-CSF expressing vaccine. These studies highlight the increased efficacy of OX40 costimulation when combined with a GM-CSF-secreting vaccine, and define a new role for OX40 costimulation of CD8+ T cells in overcoming tolerance and boosting antitumor immunity.

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“…10,14,15 The concept that blockade of coinhibitory signals can overcome resistance has generated hope that manipulating second signals may lead to enhanced antitumor immune responses. CTLA-4 blockade, for example, has been demonstrated to improve antitumor responses in several experimental cancer models, 16,17 but failed as a single agent in the treatment of poorly immunogenic tumors, 18,19 perhaps because of the common absence of its ligands B7-1 and B7-2 on tumor cells themselves.Recently, we and others demonstrated a mechanism by which tumors can evade immune destruction, the expression of programmed death ligand (PD-L1) (B7-H1) on tumor cells. 20-22 PD-L1 (B7-H1) is a B7-family member that has been described to negatively regulate T cell functions by engagement with PD-1, a CD28 family member receptor.…”

mentioning

confidence: 99%

Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

Blank

Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

272

201

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Human tumors frequently escape immune destruction, despite the presence of cyototoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumorspecific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues. The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation. Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines. However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production. Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor. In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominately in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion. ' 2006 Wiley-Liss, Inc.Key words: RCC; PD-L1; PD-1; B7-H1; melanoma Although the prognosis for patients with advanced solid tumors still remains poor, 1 a number of promising approaches, such as cancer immunotherapy, have been developed over the past decade. However, it is still an unsolved question why existing tumor-specific T cells in cancer patients fail to effectively prevent tumor progression. Inefficient T cell stimulation, either due to the absence of efficient antigen-presentation and costimulation or due to the presence of coinhibitory molecules, may contribute to this phenomenon.Data from animal models showing that CD8 1 T cells can lead to regression and rejection of solid tumors, and metastases 2 were reproduced with human cancer patients in clinical studies only partially. [3][4][5][6] Despite the fact that tumor-specific T cells can be expanded and transferred effectively and thus survive and localize into tumors, 7,8 tumor growth is not always controlled.It appears that the microenvironment of cancers protects tumor cells from immune destruction. 9,10 Increasing appreciation of costimulation (via CD28 or ICOS) and coinhibition (...

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CTLA-4 blockade synergizes with tumor-derived granulocyte– macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma

Cited by 343 publications

References 30 publications

Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction

Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction

OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

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