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Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia
Xiaoguang Wang1, Canping Chen2, Dan Vuong1
1City of Hope National Medical Center, Duarte, CA, USA.
Abstract:
Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.
Insights
Pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor, enhances CD8+ T-cell anti-lymphoma activity by increasing cytotoxicity and promoting an inflamed tumor microenvironment. This suggests NAE inhibition combined with PD-1 blockade offers a promising therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Neddylation regulates E3 Cullin-RING ligase (CRL) function, impacting substrate protein degradation.
- CD8+ T cells play a crucial role in anti-tumor immunity.
Purpose of the Study:
- To investigate the anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor.
- To elucidate the mechanism by which pevonedistat affects CD8+ T cells and the tumor microenvironment.
Main Methods:
- Treatment of patient-derived CD8+ T cells and a lymphoma model with pevonedistat.
- Assessment of T-cell function, cytotoxicity, and tumor progression.
- Genetic manipulation (B2M knockout, UBE2M loss, HIF-1α knockdown) and combination therapy (NAE inhibition with PD-1 blockade).
- Single-cell RNA sequencing (scRNA-Seq) analysis of patient samples.
Main Results:
- Pevonedistat treatment upregulated TNFα and IFNγ in CD8+ T cells, enhancing their cytotoxicity.
- Pevonedistat induced a CD8+ T-cell inflamed microenvironment and delayed tumor progression.
- Anti-tumor effects were dependent on CD8+ T cell-MHC class I interactions and mediated through HIF-1α.
- Combination of NAE inhibition and PD-1 blockade synergistically enhanced anti-tumor immunity.
Conclusions:
- Targeting NAE with pevonedistat enhances CD8+ T-cell inflammatory function against lymphoma.
- NAE inhibition modulates T-cell function in a HIF-1α-dependent manner.
- Combination therapy of NAE inhibitors with checkpoint blockade presents a rationale for enhanced anti-lymphoma strategies.
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