Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

Brenner, Ellen; Schörg, Barbara F.; Ahmetlić, Fatima; Wieder, Thomas; Hilke, Franz J.; Simon, Nadine; Schroeder, Christopher; Demidov, German; Riedel, Tanja; Fehrenbacher, Birgit; Schaller, Martin; Forschner, Andrea; Eigentler, Thomas; Niessner, Heike; Sinnberg, Tobias; Böhm, Katharina; Hömberg, Nadine; Braumüller, Heidi; Dauch, Daniel; Zwirner, Stefan; Zender, Lars; Sonanini, Dominik; Geishauser, Albert; Bauer, Jürgen; Eichner, Martin; Jarick, Katja J.; Beilhack, Andreas; Biskup, Saskia; Döcker, Dennis; Schadendorf, Dirk; Quintanilla-Martı́nez, Leticia; Pichler, Bernd J.; Kneilling, Manfred; Mocikat, Ralph; Röcken, Martin

doi:10.1038/s41467-020-14987-6

Cited by 87 publications

(89 citation statements)

References 71 publications

(120 reference statements)

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“…We have previously reported that deletions or loss of function mutations in CDKN2A increase the resistance to ICI [26]. Similarly, we find that CDKN2A deletions or loss of heterozygosity are enriched in PD (p = 0.024).…”

Section: Resistance Predictor For Immune Checkpoint Inhibitor Therapysupporting

confidence: 75%

“…Moreover, an increased risk of progressive disease at the first staging was associated with the presence of PTEN and TP53 driver mutations. Both, if mutated, are potential genetic markers for resistance to ICI [26,44].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, mutations in PTEN and amplifications of EGFR have previously been linked to resistance to ICI [25]. Mutations in TP53 have been associated with prolonged progression-free survival in lung cancer after immunotherapy [25], but also to increased ICI resistance in melanoma [26]. Indeed, we observed in our cohort that mutations in PTEN and EGFR are enriched in the PD group (24.5% and 13.3%) compared to the SD+PR group (10% and 0%), although only the difference for EGFR is borderline significant.…”

Section: Resistance Predictor For Immune Checkpoint Inhibitor Therapymentioning

confidence: 99%

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Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

Hilke

Sinnberg

Gschwind

et al. 2020

Cancers

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The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes. Melanomas of unknown primary had a similar mutation pattern and TMB to cutaneous melanoma, which hints at its cutaneous origin. Besides the typical hotspot mutation in BRAF and NRAS, we frequently observed CDKN2A deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting PDGFRA, KIT, CDK4, RICTOR, CCND2 and CHEK2. Uveal melanoma often had somatic SNVs in GNA11/Q and amplification of MYC in all cases. A significantly higher incidence of BRAF V600 mutations and EGFR amplifications, PTEN and TP53 deletions was found in patients with disease progression while on ICI. Thus, NGS might help to characterize melanoma subtypes more precisely and to identify possible resistance mechanisms to ICI therapy. Nevertheless, NGS based studies, including larger cohorts, are needed to support potential genetic ICI resistance mechanisms.

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Section: Resistance Predictor For Immune Checkpoint Inhibitor Therapysupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Resistance Predictor For Immune Checkpoint Inhibitor Therapymentioning

confidence: 99%

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Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

Hilke

Sinnberg

Gschwind

et al. 2020

Cancers

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“… 12 In line with these findings, the therapeutic potential of ICB required IFN-γ-mediated senescence induction in malignant cells that escaped from cytotoxicity, as revealed in two independent mouse models of endogenously arising cancer. 12 …”

Section: Introductionmentioning

confidence: 69%

“…Previous data indicated that tumor-specific CD4 + (Th1) cells producing interferon-γ (IFN-γ) and tumor necrosis factor (TNF) induce growth arrest of malignant cells. 13 14 It is further known that IFN-γ and TNF can activate the p16 Ink4a -Rb and the p53-p21 signaling pathways, 12 14 which induce cellular senescence, that is enduring cell cycle arrest, and that treatment with checkpoint-targeting mAbs promotes IFN-γ responses. 12 In line with these findings, the therapeutic potential of ICB required IFN-γ-mediated senescence induction in malignant cells that escaped from cytotoxicity, as revealed in two independent mouse models of endogenously arising cancer.…”

Section: Introductionmentioning

confidence: 99%

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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Loss of p14 diminishes immunogenicity in melanoma via non‐canonical Wnt signaling by reducing the peptide surface density

Wohlfarth,

Kosnopfel,

Faber

et al. 2024

Molecular Oncology

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Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin‐dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor‐suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased T cell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)‐specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA‐I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non‐canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA‐specific T cell responses by decreasing both absolute and relative MDA‐peptide presentation in melanoma.

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Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

Cited by 87 publications

References 71 publications

Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

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

Loss of p14 diminishes immunogenicity in melanoma via non‐canonical Wnt signaling by reducing the peptide surface density

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