CD4+ T lymphocytes as a primary cellular target for BAT mAb stimulation

Raiter, Annat; Rodionov, Galina; Novogrodsky, Abraham; Hardy, Britta

doi:10.1093/intimm/12.11.1623

Cited by 8 publications

(8 citation statements)

References 8 publications

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“…Autologous T cells were purified from nonadherent fraction of the buffy coat that was used to purify MDM, using nylon wool column as described earlier (22). In brief, the nonadherent cells were incubated in prewashed nylon wool at 37°C in 5% CO 2 .…”

Section: T Cell Activation Assaymentioning

confidence: 99%

The PPE18 of Mycobacterium tuberculosis Interacts with TLR2 and Activates IL-10 Induction in Macrophage

Nair

Ramaswamy

Ghosh

et al. 2009

The Journal of Immunology

189

205

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The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction. In silico docking analyses and mutation experiments indicate that PPE18 specifically interacts with the leucine rich repeat 11 approximately 15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam(3)CSK(4) known to activate predominantly ERK 1/2. When PMA-differentiated THP-1 macrophages were infected with a mutant Mycobacterium tuberculosis strain lacking the PPE18, produced poorer levels of IL-10 as compared with those infected with the wild-type strain. In contrast, an M. smegmatis strain overexpressing the PPE18 induced higher levels of IL-10 in infected macrophages. Our data indicate that the PPE18 protein may trigger an anti-inflammatory response by inducing IL-10 production.

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Section: T Cell Activation Assaymentioning

confidence: 99%

The PPE18 of Mycobacterium tuberculosis Interacts with TLR2 and Activates IL-10 Induction in Macrophage

Nair

Ramaswamy

Ghosh

et al. 2009

The Journal of Immunology

189

205

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“…Another mechanism by which tumors inhibit anti-tumor immunity is through the induction of Treg cells. Treg cells are inhibitory CD4 1 T cells that are increased in cancer patients, both peripherally and in tumors, and can form a barrier to eliciting effective immune responses [17][18][19][20][21][22]. It has been shown that anti-tumor immunity is enhanced by depletion of Treg cells with agents such as anti-CD25 and low-dose CPM [23][24][25][40][41][42].…”

Section: Pdl-1 Expression On Human Tumor Cells and The Number Of Tumomentioning

confidence: 99%

“…Treg cells are inhibitory CD4 1 T cells that are increased in cancer patients and can potentially form a barrier to eliciting effective immune response [17][18][19][20][21][22]. Not surprisingly, the inactivation or depletion of Treg cells has been actively pursued, in order to develop more potent anti-tumor immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

Anti‐PD‐1 synergizes with cyclophosphamide to induce potent anti‐tumor vaccine effects through novel mechanisms

et al. 2011

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Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination. This strategy led to complete regression of established tumors in a significant percentage of treated animals, with survival prolongation. We show for the first time that combining CT-011 and CPM significantly increases the number of vaccine-induced tumor-infiltrating CD8 1 T cells, with simultaneous decrease in infiltrating Treg cells. Interestingly, we find that CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable significant synergistic decrease of splenic and tumor-infiltrated Treg cells. Surprisingly, we find that the anti-tumor effect elicited by the combination of CT-011 and CPM is dependent on both CD8 1 and CD4 1 T-cell responses, although the antigen we used is a class I MHCrestricted peptide. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.Key words: Cancer immunotherapy . Programmed death-1 receptor . Vaccine IntroductionImmune suppression/evasion is one of the major impediments to the development of effective immune therapy for cancer. Programmed death-1 receptor (PD-1) is a member of the B7 family that is expressed on activated T cells and is found to play an important role in immune evasion. On binding its cognate ligands programmed death ligand (PDL)-1 or PDL-2, PD-1 downregulates signaling by the T-cell receptor (TCR), inducing T-cell anergy and apoptosis and thus leading to immune suppression [1][2][3][4][5][6]. Many human malignancies up-regulate PDL-1, and this upregulation has been directly correlated with immune suppression and poor prognosis in several types of cancer [4,[7][8][9][10][11]. The PD-1/PDL-1 interaction leads to suppression and apoptosis of [27,[29][30][31][32][33].Here, we hypothesize that combining inhibition of Treg cells with strategies that block the PD-1/PDL-1 interaction and vaccine would result in a potent anti-tumor immunotherapeutic strategy. CT-011 is a novel humanized IgG1 k recombinant monoclonal anti-PD-1 antibody that has been shown to promote anti-tumor immunity in animal models in a Phase I clinical trial in hematological malignancies [34].We found that PD-1 blockade with low-dose CPM, given in combination with vaccine, synergistically induces strong antigenspecific immune responses and increases CD8 1 and CD4 1 Foxp3À T-cell infiltration into the tumor, leading to a potent antitumor effect. Interestingly, we demonstrated that the efficacy of the combination relies not only on CD8 1 but...

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“…The mechanism of action of BAT determined that NK or T cells mediated the antitumor effect of BAT [35] and the primary cellular target for BAT in human peripheral blood cells were CD4 + T cells that stimulated the secretion of IFN-γ [40]. The local secretion of IFN-γ induces an anti-tumor response by recruitment of host immune cells to the tumor resulting in a successful host anti-tumor immune response.…”

Section: The Use Of Antibodies In Cancer Therapymentioning

confidence: 99%

New era in cancer immunotherapy: Twenty years to the discovery of monoclonal antibodies harnessing the immune system to eradicate tumors

Hardy¹,

Raiter²

2013

ABB

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The better understanding of the mechanism in which the immune system responds to the developing cancer provided the outcome in a new era in cancer immunotherapy. The tumor suppressive effect on the immune system is caused by negative T cell receptor signaling that abrogate immunity against the cancer cells. Novel monoclonal antibodies that target co-inhibitory receptors on T cells block the tumor induced inhibition of the immune system and enable the immune system to eradicate the tumors. The development of such antibodies started twenty years ago by the preparation of a monoclonal antibody termed BAT. A single administration of the antibody to tumor bearing mice resulted in striking anti tumor activity that was mediated by the lymphocytes. These studies provided a basis for the new era of cancer immunotherapy. The present review summarizes twenty years to the discovery of monoclonal antibodies harnessing the immune system to eradicate tumors.

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CD4+ T lymphocytes as a primary cellular target for BAT mAb stimulation

Cited by 8 publications

References 8 publications

The PPE18 of Mycobacterium tuberculosis Interacts with TLR2 and Activates IL-10 Induction in Macrophage

The PPE18 of Mycobacterium tuberculosis Interacts with TLR2 and Activates IL-10 Induction in Macrophage

Anti‐PD‐1 synergizes with cyclophosphamide to induce potent anti‐tumor vaccine effects through novel mechanisms

New era in cancer immunotherapy: Twenty years to the discovery of monoclonal antibodies harnessing the immune system to eradicate tumors

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