Oxidized low-density lipoproteins impair the pro-atherosclerotic effect of granulocyte-macrophage-colony-stimulating factor-producing T helper cells on macrophages.

T cells contribute to the pathogenesis of atherosclerosis. However, the presence and function of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (ThGM) cells in atherosclerosis development is unknown. This study aims to characterize the phenotype and function of ThGM cells in experimental atherosclerosis. Atherosclerosis was induced by feeding apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet. Aortic ThGM cells were detected and sorted by flow cytometry. The effect of oxidized low-density lipoprotein (oxLDL) on ThGM cells and the impact of ThGM cells on macrophages were evaluated by flow cytometry, quantitative RT-PCR, oxLDL binding/uptake assay, immunoblotting and foam cell formation assay. We found that GM-CSF+IFN-γ- ThGM cells existed in atherosclerotic aortas. Live ThGM cells were enriched in aortic CD4+CCR6-CCR8-CXCR3-CCR10+ T cells. Aortic ThGM cells triggered the expression of interleukin-1ß (IL-1ß), tumour necrosis factor (TNF), interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2) in macrophages. Besides, aortic ThGM cells expressed higher CD69 than other T cells and bound to oxLDL. oxLDL suppressed the cytokine expression in ThGM cells probably via inhibiting the signal transducer and activator of transcription 5 (STAT5) signalling. Furthermore, oxLDL alleviated the effect of ThGM cells on inducing macrophages to produce pro-inflammatory cytokines and generate foam cells. The nuclear receptor subfamily 4 group A (NR4A) members NR4A1 and NR4A2 were involved in the suppressive effect of oxLDL on ThGM cells. Collectively, oxLDL suppressed the supportive effect of ThGM cells on pro-atherosclerotic macrophages.

[Retracted] Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the immunofluorescence data shown in Fig. 2G, the mitochondria­ and lysosome­stained images in Fig. 3C, the JC­1 staining images in Fig. 4C and the immunofluorescence data in Fig. 5G were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Molecular Medicine Reports, or were under consideration for publication at around the same time. In view of the fact that certain of the abovementioned data had already apparently been published previously, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 3722­3734, 2018; DOI: 10.3892/mmr.2018.8371].

Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase.

CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4+ T cells. Furthermore, the absence of eEF2K in CD4+ T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4+ T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4+ T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4+ T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.

Co-Targeting Nucleus Accumbens Associate 1 and NF-κB Signaling Synergistically Inhibits Melanoma Growth.

Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma. Furthermore, the inhibition of NF-κB signaling significantly potentiates the antineoplastic activity of the NAC1 inhibition in both the cultured melanoma cells and xenograft tumors. This study identifies a novel NAC1-NF-κB signaling axis in melanoma, offering a promising new therapeutic option to treat melanoma.

NAC1 confines virus-specific memory formation of CD4+ T cells through the ROCK1-mediated pathway.

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild-type (WT) and NAC1-deficient (-/- ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T-cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK-mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1-/- CD4+ T cells restored autophagy and the activity of the AMPK-mTOR pathway. In animal experiments, adoptively transferred NAC1-/- CD4+ T cells or NAC1-/- mice challenged with VACV showed enhanced formation of VACV-specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T-cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T-cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T-cell development, which is critical for an effective immune response against pathogens.

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

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.

T Cell Response to SARS-CoV-2 Coinfection and Comorbidities.

For the past three years, COVID-19 has become an increasing global health issue. Adaptive immune cells, especially T cells, have been extensively investigated in regard to SARS-CoV-2 infection. However, human health and T cell responses are also impacted by many other pathogens and chronic diseases. We have summarized T cell performance during SARS-CoV-2 coinfection with other viruses, bacteria, and parasites. Furthermore, we distinguished if those altered T cell statuses under coinfection would affect their clinical outcomes, such as symptom severity and hospitalization demand. T cell alteration in diabetes, asthma, and hypertension patients with SARS-CoV-2 infection was also investigated in our study. We have summarized whether changes in T cell response influence the clinical outcome during comorbidities.

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

BACKGROUND: T 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. METHODS: Adoptive 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. RESULTS: Tumorous 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. CONCLUSIONS: Tumor 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 heterogeneous subsets of aortic interleukin-17A-expressing CD4+ T cells in atherosclerotic mice.

OBJECTIVES: T helper 17 (Th17) cells are involved in the inflammatory response of atherosclerosis. However, their heterogeneity in the atherosclerotic aorta remains elusive. This study was designed to identify aortic Th17 subsets. METHODS: The surface markers and transcription factors of aortic interleukin-17A (IL-17A)-expressing T cells were determined by flow cytometry in an ApoE-deficient mouse atherosclerotic model. Viable aortic IL-17A-expressing T cell subsets were isolated by flow cytometry on the basis of surface markers, followed by characterizing their transcription factors by either flow cytometry or real-time RT-PCR. The effect of aortic IL-17A-expressing T cell subsets on aortic endothelial cells was determined in vitro. RESULTS: C-X-C Motif Chemokine Receptor 3 (CXCR3), interleukin-17 receptor E (IL-17RE), CD200, and C-C Motif Chemokine Receptor 4 (CCR4) marked three subsets of aortic IL-17A-expressing T cells: CXCR3+IL-17RElowCD200+CCR4- T cells expressing T-box protein expressed in T cells (T-bet) and interferon-gamma (IFN-γ), CXCR3+IL-17RElowCD200+CCR4+ T cells expressing T-bet but fewer IFN-γ, and CXCR3-IL-17REhighCD200+CCR4+ T cells expressing very low T-bet and no IFN-γ. Based on these markers, viable aortic Th17 cells, Th17.1 cells, and transitional Th17.1 cells were identified. Both Th17.1 cells and transitional Th17.1 cells were more proliferative than Th17 cells. Compared with Th17 cells, Th17.1 cells plus transitional Th17.1 cells induced higher expression of C-X-C motif chemokine ligand 1 (CXCL1), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine 5 (CXCL5), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in aortic endothelial cells. CONCLUSION: IL-17A-expressing CD4+ T cells were heterogeneous in atherosclerotic aortas.

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

Nucleus accumbens-associated protein 1 (NAC1) is a transcription co-factor that has been shown to possess multiple roles in stem cell and cancer biology. However, little is known about its roles in regulation of the immune system. In the current study, we observed that expression of NAC1 impacted the survival of CD8+ T cells in vitro. NAC1-/- CD8+ T cells displayed lower metabolism, including reduced glycolysis and oxidative phosphorylation. In vivo, compared with wild-type (WT) mice, NAC1-/- mice produced a lower response to vaccinia virus (VACV) infection, and viral antigen (Ag)-specific CD8+ T cells decreased more slowly. Additionally, we observed that the NAC1-/- mice demonstrated a stronger memory formation of viral Ag-specific CD8+ T cells post-viral infection. Mechanically, we identified that compared with WT CD8+ T cells, the Interferon Regulatory Factor 4 (IRF4), a key transcription factor in T cell development, was highly expressed in NAC1-/- CD8+ T cells, insinuating that IRF4 could be a critical regulatory target of NAC1 in the memory formation of CD8+ T cells. Our results indicate that NAC1 restrains the memory formation of CD8+ T cells by modulating IRF4, and targeting NAC1 may be exploited as a new approach to boosting CD8+ T cell memory.

NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance.

We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (Tregs) and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4+ Tregs that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of Tregs with the proinflammatory cytokines interleukin-1ß or tumor necrosis factor-α induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3. These findings imply that NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.

ETS variant transcription factor 6 enhances oxidized low-density lipoprotein-induced inflammatory response in atherosclerotic macrophages via activating NF-κB signaling.

Objectives: Macrophages play a critical role in atherosclerosis by contributing to plaque development, local inflammation, and thrombosis. Elucidation of the molecular cascades in atherosclerotic macrophages is important for preventing and treating atherosclerosis. This study aims to deepen the understanding of the mechanisms that regulate the function of aorta macrophage in atherosclerosis. Methods: In the current study, the expression and function of ETS variant transcription factor 6 (ETV6) in aorta macrophages in a mouse atherosclerosis model. Aorta macrophages were enriched by flow cytometry. ETV6 expression was analyzed by quantitative RT-PCR. The role of ETV6 in macrophage-mediated pro-inflammatory response was evaluated both in vitro and in vivo after ETV6 silencing. Results: A remarkable elevation of ETV6 in aorta macrophages of atherosclerotic mice was observed. In addition, in vitro analysis indicated that oxidized low-density lipoprotein (oxLDL) up-regulated ETV6 in macrophages via the NF-κB pathway. ETV6 silencing suppressed oxLDL-induced expression of IL-1ß, IL-6, and TNF-α in macrophages in vitro. However, ETV6 silencing did not impact the uptake of either oxLDL or cholesterol by macrophages. Furthermore, ETV6 silencing suppressed oxLDL-induced activation of the NF-κB pathway in macrophages, as evidenced by less phosphorylation of IKKß and NF-κB p65, more cytoplasmic IκBα, and lower nuclear NF-κB p65. Moreover, ETV6 silencing inhibited the production of IL-1ß and TNF-α in aorta macrophages in vivo. Conclusion: ETV6 supports macrophage-mediated inflammation in atherosclerotic aortas. This is a novel mechanism regulating the pro-inflammatory activity of atherosclerotic macrophages.

Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8+ T cells.

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8+ T cells. CD8+ T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8+ T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8+ T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8+ T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8+ T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8+ T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.

Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase.

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.

Metabolic Reprogramming and Reactive Oxygen Species in T Cell Immunity.

T cells undergo metabolic reprogramming and multiple biological processes to satisfy their energetic and biosynthetic demands throughout their lifespan. Several of these metabolic pathways result in the generation of reactive oxygen species (ROS). The imbalance between ROS generation and scavenging could result in severe damage to the cells and potential cell death, ultimately leading to T cell-related diseases. Interestingly, ROS play an essential role in T cell immunity. Here, we introduce the important connectivity between T cell lifespan and the metabolic reprogramming among distinct T cell subsets. We also discuss the generation and sources of ROS production within T cell immunity as well as highlight recent research concerning the effects of ROS on T cell activities.

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells.

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

An optimized protocol for the generation of HBV viral antigen-specific T lymphocytes from pluripotent stem cells.

In T cell-based cancer immunotherapy, tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) can specifically target tumor Ags on malignant cells. This promising approach drove us to adopt this strategy of T cell transfer (ACT)-based immunotherapy for chronic viral infections. Here, we describe the generation of hepatitis B virus (HBV) Ag-specific CTLs from induced pluripotent stem cells (iPSCs), i.e., iPSC-CTLs. Ag-specific iPSC-CTLs can target HBV Ag+ cells and infiltrate into the liver to suppress HBV replication in a murine model. For complete details on the use and execution of this protocol, please refer to Haque et al. (2020).

Autophagy in T-cell differentiation, survival and memory.

Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival by regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival and memory, and its implication in immunotherapy for various diseases.

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺.

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.

Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors.

Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.