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

Abstract

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.

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

“…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.…”

“…We and others previously demonstrated the oncogenic role of NACC1 in various types of cancer and in supporting cell survival under hypoxia conditions [39]. More recently, we showed that NAC1 expression in melanoma cells promotes their evasion from immune surveillance [40]. Thus, we asked whether this transcription co-factor has any effects on those signature genes in TNBC cells.…”

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

“…[ 37 ]. More recently, we showed that NAC1 (encoded by the NACC1) expression in melanoma cells promotes their evasion from immune surveillance [ 38 ]. Thus, we asked whether this transcription co-factor has any effects on those signature genes in TNBC cells.…”

“…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.…”

Immunotherapy: A new target for cancer cure (Review)

“…It can hypothesized that the immune system recognizes and destroys tumor cells expressing strong immunogenicity, while tumor cells with weak (or no) immunogenicity selectively survive and eventually form tumors. Immunotherapy may become the most advantageous tool to overcome this ( 14 ). The relationship between the immune system and tumors is complicated.…”