CTLA-4 Blockade Reverses CD8+ T Cell Tolerance to Tumor by a CD4+ T Cell– and IL-2-Dependent Mechanism

Shrikant, Protul; Khoruts, Alexander; Mescher, Matthew F.

doi:10.1016/s1074-7613(00)80123-5

Cited by 273 publications

(226 citation statements)

References 40 publications

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“…The potential contribution of T cell immunity in the therapeutic effectiveness of the combination regimen investigated in this study is further supported by the highest degree of CD3 C infiltrating cells identified in TS/A tumors from mice treated with 5-AZA-CdR and mAb 9H10. Consistent with previous observations demonstrating that tumor-specific immune responses induced by immune checkpoint blockade depend on both CD4 C and CD8 C T cells, 22,23 the lymphocyte tumor infiltration comprised both CD4 C and CD8 C T cells.…”

Section: Discussionsupporting

confidence: 92%

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

et al. 2015

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The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2 0 -deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p D 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylationsustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3 C lymphocytes, which included both CD8 C and CD4 C T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients.

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Section: Discussionsupporting

confidence: 92%

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

et al. 2015

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“…First, CTLA-4 blockade may augment responsiveness by facilitating the participation in the response of T cells with TCRs that have high affinity for the p53 261-269 epitope. Consistent with this possibility, it has been described that anti-CTLA-4 treatment may reverse CD8 ϩ T cell tolerance to a tumor-expressed Ag by reversing anergy (21). Alternatively, the presence of anti-CTLA-4 may result in the enhanced expansion of the low-avidity p53-specific CTL that are usually found to respond in these mice.…”

Section: Anti-ctla-4 Treatment Augments the Frequency Of The Lowaffinmentioning

confidence: 68%

“…However, the precise mechanism by which CTLA-4 blockade augments antitumor responses in vivo remains unclear. Whereas some studies have shown a direct effect by anti-CTLA-4 on enhancement of CD8 ϩ T cell responses in vivo (19,20), other studies suggest that this may be indirect and mediated through the influence of anti-CTLA-4 on CD4 ϩ T cell help (21). There is also controversy regarding the ability of anti-CTLA-4 to prevent and/or reverse T cell tolerance in vivo (21)(22)(23).…”

mentioning

confidence: 99%

CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen

Hernández

Sherman

2001

The Journal of Immunology

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p53 is an attractive target for cancer immunotherapy because it is overexpressed in a high proportion of many different types of tumors. However, it is also expressed in normal tissues and acts as a toleragen in vivo. Previously, detailed examination of the repertoire specific for the murine p53261–269 epitope in conventional and p53-deficient mice demonstrated that because of expression of p53, the CD8+ T cells that respond to this epitope express low-affinity TCRs. It has been reported that tolerance to tumor Ags can be broken by in vivo administration of anti-CTLA-4 mAb. With the goal of overriding tolerance and achieving optimal activation of p53-specific CTL, the current study has assessed the effect of anti-CTLA-4 mAb on the p53-specific repertoire. It was found that blockade of CTLA-4 engagement at the time of antigenic stimulation induced a vigorous amplification of the CTL responses to p53 as well as proportionate expansion of the memory T cell pool. This effect was dependent on the presence of CD4+ T cell help and correlated with an enhancement of helper function. However, anti-CTLA-4 treatment did not enhance the avidity of the resultant p53-specific CTL populations and, therefore, could not reverse this important consequence of tolerance.

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“…In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic viral infections [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Caserta

Alessi²,

Basso³

et al. 2010

Eur J Immunol

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It is well established that tumours hinder both natural and vaccine-induced tumourspecific CD4 1 T-cell responses. Adoptive T-cell therapy has the potential to circumvent functional tolerance and enhance anti-tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8 1 T cells are currently available, data on tumour-specific CD4 1 T cells remain scarce. We report here that CD4 1 T cells sensitized to tumour-associated Ag in vivo, proliferate in vitro in response to IL-7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory-like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumoursensitized T cells among other memory and naive lymphocytes following exposure to IL-7. Also IL-2, previously used to expand anti-tumour CTL, promotes tumour-specific CD4 1 T-cell accumulation. However, IL-7 is superior to IL-2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4 1 T cells to confer therapeutic efficacy upon transplantation in tumour-bearing hosts. Together our data support a unique role for IL-7 in retrieving memory-like CD4 1 T cells suitable for adoptive T-cell therapy.Key words: Adoptive T-cell therapy . Cytokines . T helper cells . Tumour immunology Supporting Information available online IntroductionAdoptive cell therapy (ACT) with tumour-specific CD8 1 T lymphocytes has become one of the most promising approaches in cancer therapy. Rosenberg et al. first demonstrated the possibility to expand tumour-specific cytotoxic CD8 1 lymphocytes (CTL) from tumour lesions in high doses of IL-2 [1]. These authors later showed that the state of lymphocyte differentiation, induced in the presence of common g-chain receptor cytokines, is critical for therapeutic efficacy [2,3]. In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic 470viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL. Thus, CD4 1 T cells have not been widely exploited in ACT as well as the properties (i.e. homing potential, functionality, and survival) that CD4 1 T cells might require for successful applications in ACT are much less known than in the case for CD8 1 CTL.A large, still not definitive, amount of ...

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CTLA-4 Blockade Reverses CD8+ T Cell Tolerance to Tumor by a CD4+ T Cell– and IL-2-Dependent Mechanism

Cited by 273 publications

References 40 publications

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

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CTLA-4 Blockade Reverses CD8+ T Cell Tolerance to Tumor by a CD4+ T Cell– and IL-2-Dependent Mechanism

Cited by 273 publications

References 40 publications

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

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IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells