Expression of NAC1 Restrains the Memory Formation of CD8+ T Cells during Viral Infection

Wang, Liqing; Kumar, Anil; Das, Jugal Kishore; Ren, Yijie; Peng, Hao-Yun; Ballard, Darby J; Xiong, Xiaofang; Davis, Jacob Rance; Ren, Xingcong; Yang, Jin-Ming; Song, Jianxun

doi:10.3390/v14081713

Cited by 13 publications

(11 citation statements)

References 28 publications

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“…More recently, we reported that NAC1 expression in melanoma cells was critical for immune evasion [40] and that NACC1 expression negatively regulates the suppressive activity of Tregs [54] and CD8 + memory T-cells [55]. The current study suggests that NAC1, likely through regulation of the identified signature genes, has a role in immunosuppressive TME.…”

Section: Discussionsupporting

confidence: 54%

Identification of a NACC1-Regulated Gene Signature Impli-Cated in the Features of Triple-Negative Breast Cancer

Liu¹,

Ngule²,

Hemati³

et al. 2023

Preprint

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Triple-negative breast cancer (TNBC), characterized by deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotype such as tumor heterogeneity and therapy resistance remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approach, we found 55-up and 9-down regulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration, was positively correlated with status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Also, enhanced infiltration of immunosuppressive cells was positively correlated with the expression of these 5 genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expressions of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment.

show abstract

Section: Discussionsupporting

confidence: 54%

Identification of a NACC1-Regulated Gene Signature Impli-Cated in the Features of Triple-Negative Breast Cancer

Liu¹,

Ngule²,

Hemati³

et al. 2023

Preprint

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“…We recently reported that expression of NAC1 negatively regulates the suppressive activity of CD4 + T regs 26 and the formation of CD8 + memory T cells. 29 In this study, we identified tumorous NAC1 as a critical determinant of antitumor immunity, and NAC1 promotes immune evasion through LDHAmediated production of LA, contributing to an acidic and immune-suppressive TME.…”

Section: Discussionmentioning

confidence: 87%

“…15 We Open access recently reported that expression of NAC1 negatively regulates the suppressive activity of CD4 + T regs 26 and the formation of CD8 + memory T cells. 29 Although several pathways, including NAC1, are known to promote metabolic reprogramming in tumor cells, whether and how they affect antitumor immunity remains largely unclear.…”

Section: Discussionmentioning

confidence: 99%

Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion

Ren

Kumar

Das

et al. 2022

J Immunother Cancer

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BackgroundT cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME.MethodsAdoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1. The effects of NAC1 expression on immune evasion in tumor cells were assessed in vitro and in vivo. CRISPR/Cas9, glycolysis analysis, retroviral transduction, quantitative real-time PCR, flow cytometric analysis, immunoblotting, database analyses were used to screen the downstream target and underlying mechanism of NAC1 in tumor cells.ResultsTumorous expression of NAC1 negatively impacts the CTL-mediated antitumor immunity via lactate dehydrogenase A (LDHA)-mediated suppressive TME. NAC1 positively regulated the expression of LDHA at the transcriptional level, which led to higher accumulation of lactic acid in the TME. This inhibited the cytokine production and induced exhaustion and apoptosis of CTLs, impairing their cell-killing ability. In the immunocompetent and immunodeficient mice, NAC1 depleted melanoma tumors grew significantly slower and had an elevated infiltration of tumor Ag-specific CTLs following ACT, compared with the control groups.ConclusionsTumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic acid production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy, such as the ACT of CTLs.

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“…NAC1 expression in melanoma cells was recently reported by us to be essential for immune evasion. [ 38 ] and that NACC1 expression negatively regulates the suppressive activity of Tregs [ 53 ] and CD8 + memory T-cells [ 54 ]. The current study suggests that NAC1, likely through the regulation of the identified signature genes, has a role in immunosuppressive TME.…”

Section: Discussionmentioning

confidence: 99%

Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer

et al. 2023

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment.

show abstract

Expression of NAC1 Restrains the Memory Formation of CD8+ T Cells during Viral Infection

Cited by 13 publications

References 28 publications

Identification of a NACC1-Regulated Gene Signature Impli-Cated in the Features of Triple-Negative Breast Cancer

Identification of a NACC1-Regulated Gene Signature Impli-Cated in the Features of Triple-Negative Breast Cancer

Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion

Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer

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