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Inhibition of NFE2L1 Enables the Tumor-Associated Macrophage Polarization and Enhances Anti-PD1 Immunotherapy in
Qun Zhang1, Qiusi Tian2, Rongzhen Deng1
1The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, Chongqing, China.
Background And Objectives:
A pivotal role of cancer (e.g., glioma) microenvironment is primarily executed by tumor-associated macrophages (TAMs) in facilitating cancer immune evasion and even resisting immunotherapies. However, the molecular base for governing such functionality of TAMs remains poorly understood. Thereby, we here explore the impact of such a key regulatory transcription factor NFE2L1 (also called Nrf1) on glioma-relevant TAMs.
Methods:
A set of combining in vivo and in vitro experimental approaches, e.g., by utilizing CRISPR-Cas9 and overexpression plasmids to modulate NFE2L1 expression, and the resulting phenotypic changes in TAMs were evaluated. Besides, immunofluorescence, RT-qPCR and flow cytometry were conducted to assay the infiltration of various immune cells, such as CD8+ T cells and M1-type macrophages, in the glioma microenvironment, as well as their therapeutic response to anti-PD1 treatment.
Results:
Deficiency of NFE2L1 causes a unique phenotypic switch in the TAMs from its pro-cancer M2-type to another anti-cancer M1-type, thereby inhibiting malignant progression of glioma. Such NFE2L1-deficiency leads to significantly increases of CD8+ T cells and M1 macrophages within tumor tissues of glioma and hence enhances its sensitivity to anti-PD1 therapy. Further experimental evidence has provided revealing a synergistic efficacy triggered by combined therapy of CD38 inhibitor with PD1 antibodies, significantly inhibited tumor growth, compared to that of their monotherapy. The mechanistic study unraveled that NFE2L1 enables for directly binding to those ARE sites within the promoter regions of both CD38 and PD-L1 genes in order to govern their transcriptional expression.
Conclusions:
The aberrant role of NFE2L1 in the malignant progression of glioma was discovered in this study. It is of crucial significance to emphasize the potential of NFE2L1 inhibition as a strategic approach to enhance the efficacy of immunotherapeutic intervention. Overall, this discovery holds a substantial promise for advancement of innovative combination therapies, potentially enhancing treatment outcomes for individuals afflicted with glioma.
Insights
Inhibiting NFE2L1 transforms tumor-associated macrophages (TAMs) to an anti-cancer M1 type, enhancing glioma immunotherapy. This finding supports NFE2L1 inhibition for improved combination therapies against glioma.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumor-associated macrophages (TAMs) are key players in glioma immune evasion and immunotherapy resistance.
- The molecular mechanisms governing TAM functionality in the glioma microenvironment are not fully understood.
- Nuclear factor erythroid 2-related factor 1 (NFE2L1/Nrf1) is a transcription factor whose role in glioma-associated TAMs requires investigation.
Purpose of the Study:
- To investigate the impact of the transcription factor NFE2L1 on glioma-associated TAMs.
- To explore the potential of modulating NFE2L1 expression for enhancing anti-glioma immunity and immunotherapy response.
Main Methods:
- Utilized in vivo and in vitro experimental approaches, including CRISPR-Cas9 and overexpression plasmids to manipulate NFE2L1 levels in TAMs.
- Assessed phenotypic changes in TAMs and immune cell infiltration (CD8+ T cells, M1 macrophages) via immunofluorescence, RT-qPCR, and flow cytometry.
- Evaluated therapeutic responses to anti-PD1 treatment and combination therapies.
Main Results:
- NFE2L1 deficiency induced a switch in TAMs from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype, inhibiting glioma progression.
- NFE2L1 deficiency increased CD8+ T cell and M1 macrophage infiltration in gliomas, enhancing sensitivity to anti-PD1 therapy.
- Combined therapy with a CD38 inhibitor and PD1 antibodies showed synergistic efficacy, significantly inhibiting tumor growth.
- Mechanistically, NFE2L1 directly binds to promoter regions of CD38 and PD-L1, regulating their transcription.
Conclusions:
- NFE2L1 plays a critical role in promoting glioma progression through its aberrant function in TAMs.
- Inhibiting NFE2L1 represents a promising strategy to augment the effectiveness of cancer immunotherapy.
- This research paves the way for developing novel combination therapies to improve treatment outcomes for glioma patients.
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