The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

Scheuerpflug, Anne; Ahmetlić, Fatima; Bauer, Vera; Riedel, Tanja; Röcken, Martin; Mocikat, Ralph

doi:10.1007/s00262-020-02767-6

Cited by 13 publications

(12 citation statements)

References 35 publications

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“…Thus, we recently showed that DCs are also functionally modulated and thereby have impact on anti-tumor T-cell responses during ICB. 37 In contrast, macrophages did not show phenotypic or functional changes during ICB treatment in an endogenous tumor model. 12 Further analyses of the complex alterations of the cellular network during therapy with checkpoint inhibitors are warranted.…”

Section: Discussionmentioning

confidence: 89%

Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

Ahmetlić

Fauser

Riedel

et al. 2021

J Immunother Cancer

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BackgroundAlthough antibodies blocking immune checkpoints have already been approved for clinical cancer treatment, the mechanisms involved are not yet completely elucidated. Here we used a λ-MYC transgenic model of endogenously growing B-cell lymphoma to analyze the requirements for effective therapy with immune checkpoint inhibitors.MethodsGrowth of spontaneous lymphoma was monitored in mice that received antibodies targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein-4, and the role of different immune cell compartments and cytokines was studied by in vivo depletion experiments. Activation of T and natural killer cells and the induction of tumor senescence were analyzed by flow cytometry.ResultsOn immune checkpoint blockade, visible lymphomas developed at later time points than in untreated controls, indicating an enhanced tumor control. Importantly, 20% to 30% of mice were even long-term protected and did never develop clinical signs of tumor growth. The therapeutic effect was dependent on cytokine-induced senescence in malignant B cells. The proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor (TNF) were necessary for the survival benefit as well as for senescence induction in the λ-MYC model. Antibody therapy improved T-cell functions such as cytokine production, and long-time survivors were only observed in the presence of T cells. Yet, NK cells also had a pronounced effect on therapy-induced delay of tumor growth. Antibody treatment enhanced numbers, proliferation and IFN-γ expression of NK cells in developing tumors. The therapeutic effect was fully abrogated only after depletion of both, T cells and NK cells, or after ablation of either IFN-γ or TNF.ConclusionsTumor cell senescence may explain why patients responding to immune checkpoint blockade frequently show stable growth arrest of tumors rather than complete tumor regression. In the lymphoma model studied, successful therapy required both, tumor-directed T-cell responses and NK cells, which control, at least partly, tumor development through cytokine-induced tumor senescence.

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Section: Discussionmentioning

confidence: 89%

Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

Ahmetlić

Fauser

Riedel

et al. 2021

J Immunother Cancer

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“…These findings clearly demonstrated that interfering with negative regulators of the immune system either expressed on certain immune cells (i.e., LAG-3) or on tumor cells (i.e., PD-L1) is able to restore an anti-tumor response that induces protective cancer control through the senescence barrier that leads to a stable growth arrest instead of a complete regression. Recent reports further showed the consequences of immune checkpoint blockade (ICB) on other cell types upon treatment in a mouse lymphoma model [126,127]. The antibodies used for ICB had, for instance, favorable effects on immune cells.…”

Section: Induction Of Senescence and Apoptosismentioning

confidence: 99%

“…Moreover, ICB also exerted an influence on DCs: in response to IFNγ produced by T cells and NKs, tumor-infiltrating DCs expressed more co-stimulatory molecules and a higher IL-12/IL-10 ratio. Both effects favored T cell-based immunity, as the DCs showed an improved capability of presentation and the secretion of factors that favor a Th1 cell anti-tumor immune response [127]. Although ICB is generally associated with improved therapeutic effects, and many cancer patients could already benefit from its application, there are still variations in the treatment response that rely on several factors, such as alterations of the TME and the immune system, including the occurrence of immuno-senescence, which is subject of the next section [94,128].…”

Section: Induction Of Senescence and Apoptosismentioning

confidence: 99%

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

Rentschler

Braumüller

Briquez

et al. 2022

Cancers

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In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system’s ability to establish “defensive walls” around tumors also places the tumor microenvironment into the fight against cancer. Those “defensive walls” isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease.

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“…The contribution of tumor-associated DCs to anti-PD-L1 therapies was further supported by the fact that patients with renal cell carcinoma or lung cancer treated with PD-L1 blockade (atezolizumab) experienced clinical benefit in the presence of high level of the DC gene signature, thus highlighting the importance of detecting the amount of DCs to support decision-making on treatment option [131]. These recent findings suggest that ICB therapy is effective not only by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses [132], and that blocking the PD-1 pathway early with immune checkpoint inhibitors, at the time of priming and expansion of memory T cells, could be critical for enhancing antitumor immunity.…”

Section: Pd-l1 On Dcs and Immune Checkpoint Blockade Therapiesmentioning

confidence: 99%

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

Lucarini

Tempora

D’Amico

et al. 2021

Cancers

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Tumor-infiltrating CD8+ T cells have been shown to play a crucial role in controlling tumor progression. However, the recruitment and activation of these immune cells at the tumor site are strictly dependent on several factors, including the presence of dendritic cells (DCs), the main orchestrators of the antitumor immune responses. Among the various DC subsets, the role of cDC1s has been demonstrated in several preclinical experimental mouse models. In addition, the high density of tumor-infiltrating cDC1s has been associated with improved survival in many cancer patients. The ability of cDC1s to modulate antitumor activity depends on their interaction with other immune populations, such as NK cells. This evidence has led to the development of new strategies aimed at increasing the abundance and activity of cDC1s in tumors, thus providing attractive new avenues to enhance antitumor immunity for both established and novel anticancer immunotherapies. In this review, we provide an overview of the various subsets of DCs, focusing in particular on the role of cDC1s, their ability to interact with other intratumoral immune cells, and their prognostic significance on solid tumors. Finally, we outline key therapeutic strategies that promote the immunogenic functions of DCs in cancer immunotherapy.

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The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

Cited by 13 publications

References 35 publications

Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

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