Targeting monoamine oxidase A for T cell–based cancer immunotherapy

2021 ◽  
Vol 6 (59) ◽  
pp. eabh2383
Author(s):  
Xi Wang ◽  
Bo Li ◽  
Yu Jeong Kim ◽  
Yu-Chen Wang ◽  
Zhe Li ◽  
...  
Keyword(s):  
T Cell ◽  
Monoamine Oxidase ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Monoamine Oxidase A ◽  
T Cell Immunity ◽  
Dependent Manner ◽  
Cell Immunity ◽  
Mao A ◽  
And Behavior

Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the Maoa gene in tumor-infiltrating immune cells. Maoa knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cell–dependent manner. Combining MAOI and anti–PD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral MAOA expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy.

scholarly journals Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1170
Author(s):  
Mithunah Krishnamoorthy ◽  
Lara Gerhardt ◽  
Saman Maleki Maleki Vareki
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Cancer Progression ◽  
Suppressor Cells ◽  
T Cell Immunity ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Immunity ◽  
Promote Tumor Growth

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

scholarly journals Microgravity Inhibits Resting T Cell Immunity in an Exposure Time-Dependent Manner

2014 ◽  
Vol 11 (1) ◽  
pp. 87-96 ◽  
Author(s):  
Haiying Luo ◽  
Chongzhen Wang ◽  
Meifu Feng ◽  
Yong Zhao
Keyword(s):  
T Cell ◽  
Exposure Time ◽  
T Cell Immunity ◽  
Time Dependent ◽  
Dependent Manner ◽  
Cell Immunity

scholarly journals Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy

2010 ◽  
Vol 16 (19) ◽  
pp. 4695-4701 ◽  
Author(s):  
Luca Gattinoni ◽  
Yun Ji ◽  
Nicholas P. Restifo
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
T Cell Immunity ◽  
Cell Immunity

scholarly journals Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity.

1991 ◽  
Vol 88 (9) ◽  
pp. 3535-3539 ◽  
Author(s):  
M. N. Teng ◽  
B. H. Park ◽  
H. K. Koeppen ◽  
K. J. Tracey ◽  
B. M. Fendly ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Growth ◽  
Tumor Necrosis ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Inhibition Of Tumor Growth ◽  
Necrosis Factor

The double-edge role of B cells in mediating antitumor T-cell immunity: Pharmacological strategies for cancer immunotherapy

2016 ◽  
Vol 36 ◽  
pp. 73-85 ◽  
Author(s):  
Jing-Zhang Wang ◽  
Yu-Hua Zhang ◽  
Xin-Hua Guo ◽  
Hong-Yan Zhang ◽  
Yuan Zhang
Keyword(s):  
T Cell ◽  
B Cells ◽  
Cancer Immunotherapy ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Double Edge

scholarly journals Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Chen Wang ◽  
Xi Wang ◽  
Jiaji Yu ◽  
Feiyang Ma ◽  
Zhe Li ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Cancer Immunotherapy ◽  
Macrophage Polarization ◽  
Monoamine Oxidase A ◽  
Tumor Associated Macrophage ◽  
Mao A ◽  
Immunosuppressive Tumor Microenvironment ◽  
The Brain ◽  
Deficient Mice ◽  
Poor Patient Survival

AbstractTargeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

scholarly journals Plasmacytoid Dendritic Cells and Cancer Immunotherapy

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 222
Author(s):  
Chunmei Fu ◽  
Li Zhou ◽  
Qing-Sheng Mi ◽  
Aimin Jiang
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Vaccines ◽  
Critical Role ◽  
Dependent Manner ◽  
Cell Immunity ◽  
New Findings ◽  
Dc Vaccines ◽  
Therapeutic Cancer Vaccines

Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy.

scholarly journals The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

2021 ◽  
Author(s):  
David J. Hamelin ◽  
Dominique Fournelle ◽  
Jean-Christophe Grenier ◽  
Jana Schockaert ◽  
Kevin Kovalchik ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Immunity ◽  
First Year ◽  
Human Populations ◽  
Dependent Manner ◽  
T Cell Epitopes ◽  
Diverse Range ◽  
Mutational Landscape ◽  
Cell Immunity ◽  
The Impact

The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

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