Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery

Kono, Michihisa; Kumai, Takumi; Hayashi, Ryusuke; Yamaki, Hidekiyo; Komatsuda, Hiroki; Wakisaka, Risa; Nagato, Toshihiro; Ohkuri, Takayuki; Kosaka, Akemi; Ohara, Kenichi; Kishibe, Kan; Takahara, Miki; Katada, Akihiro; Hayashi, Tatsuya; Celis, Esteban; Kobayashi, Hiroya; Harabuchi, Yasuaki

doi:10.1007/s00262-021-02940-5

Cited by 14 publications

(19 citation statements)

References 41 publications

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“…Our study found HA mainly occurred in genes involved in the cell cycle and RTK-RAS-PI3K pathways, which are known to be involved in tumorigenesis. Previous studies have reported that amplifications of cell cycle driver genes and RTK-RAS-PI3K pathway genes, such as CCND1, MDM2, MET and VEGF-A, were associated with a lack of response to or poor survival benefit with anti-PD(L)-1 treatment [38][39][40][41][42][43][44]. In addition, reduced interferon response, low T cell abundance, poor T cell activity and a more immunosuppressive tumor microenvironment (enriched TGF-β signaling, hypoxia signaling) were observed in tumors with amplified genes in these two pathways, suggesting that hyperamplification in cell cycle/RTK-RAS-PI3K pathways may be a key point to drive anti-PD(L)-1 resistance through inducing both an immunosuppressive tumor microenvironment and malignancy hallmarks [40,41,[44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

et al. 2022

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Background In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response. Methods All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (N = 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity [TAP] ≥ 5%), interferon gamma (IFNγ)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab. Results A moderate association was observed between PD-L1 TAP ≥ 5%, IFNγ gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA − had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors. Conclusions In GEA, PD-L1 positivity, IFNγ-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA − may help identify patients more likely to benefit from PD-1 blockade.

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Section: Discussionmentioning

confidence: 99%

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

et al. 2022

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“…Similarly, MAP kinase inhibitors increase MHC classes I and class II expression and potentiate the antitumor effects of ICIs [96]. Mouse double minute 2 inhibitors also augment antitumor T-cell responses through the upregulation of MHCs [29]. These results suggest that tumors actively inhibit antitumor T-cells through decreased antigen presentation; additionally, the inhibition of the signaling that downregulates MHCs can be a novel adjuvant strategy to augment T-cell responses by peptide vaccines.…”

Section: Modern Adjuvantsmentioning

confidence: 90%

“…In classical cancer immunotherapy, CTLs are focused on as the "killer" T-cells against tumors, and HTLs are considered as the "helper" T-cells that support the cytotoxic function of CTLs. Although CTLs are potent in killing tumors, HTLs can directly exert antitumor effects through the production of cytokines such as IFN-γ, TNF-α, granzyme-B, and perforin [29][30][31]. Moreover, several reports have shown that HTLs are more important than CTLs in cancer immunotherapy by the direct tumor killing and education of CTLs or natural killer (NK) cells [32][33][34][35].…”

Section: Selecting Tumor Antigens As a Source Of Vaccinesmentioning

confidence: 99%

Antitumor Peptide-Based Vaccine in the Limelight

et al. 2022

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The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

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“…CD4+ T cells that are reactive against a selected peptide from MDM2 have been developed and showed promising effects against cancer progression. When tested in combination with nutlin-3, the expression of MDM2 in cancer cells was increased which in turn increases the anti-tumour response of the CD4+ T cells ( 82 ).…”

Section: Molecules That Target Wtp53 Hnsccmentioning

confidence: 99%

Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments

et al. 2022

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TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV+ cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.

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Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery

Cited by 14 publications

References 41 publications

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

Antitumor Peptide-Based Vaccine in the Limelight

Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments

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