SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors.

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-ß promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-ß signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-ß-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-ß receptor I and abrogated the interplay between the TGF-ß and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-ß. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.

Abnormal low expression of SFTPC promotes the proliferation of lung adenocarcinoma by enhancing PI3K/AKT/mTOR signaling transduction.

The abnormality of surfactant protein C (SFTPC) has been linked to the development of a number of interstitial lung diseases, according to mounting evidence. Nonetheless, the function and mechanism of SFTPC in the biological progression of lung adenocarcinoma (LUAD) remain unclear. Analysis of public datasets and testing of clinical samples suggested that SFTPC expression was abnormally low in LUAD, which was associated with the onset and poor prognosis of LUAD. The SFTPC-related risk score was derived using least absolute shrinkage and selection operator Cox regression as well as multivariate Cox regression. The risk score was highly correlated with tumor purity and tumor mutation burden, and it could serve as an independent prognostic indicator for LUAD. Low-risk LUAD patients may benefit more from CTLA-4 or/and PD-1 inhibitors. Overall, the risk score is useful for LUAD patient prognostication and treatment guidance. Moreover, in vitro and in vivo experiments demonstrated that SFTPC inhibits the proliferation of LUAD by inhibiting PI3K/AKT/mTOR signaling transduction. These results reveal the molecular mechanism by which SFTPC inhibits the proliferation of LUAD and suggest that SFTPC could be a new therapeutic target for LUAD.

Integrated bioinformatics analysis of the NEDD4 family reveals a prognostic value of NEDD4L in clear-cell renal cell cancer.

The members of the Nedd4-like E3 family participate in various biological processes. However, their role in clear cell renal cell carcinoma (ccRCC) is not clear. This study systematically analyzed the Nedd4-like E3 family members in ccRCC data sets from multiple publicly available databases. NEDD4L was identified as the only NEDD4 family member differentially expressed in ccRCC compared with normal samples. Bioinformatics tools were used to characterize the function of NEDD4L in ccRCC. It indicated that NEDD4L might regulate cellular energy metabolism by co-expression analysis, and subsequent gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A prognostic model developed by the LASSO Cox regression method showed a relatively good predictive value in training and testing data sets. The result revealed that NEDD4L was associated with biosynthesis and metabolism of ccRCC. Since NEDD4L is downregulated and dysregulation of metabolism is involved in tumor progression, NEDD4L might be a potential therapeutic target in ccRCC.

Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab.

Despite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-ß (TGF-ß) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-ß and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.

Association between ABCB1 (3435C>T) polymorphism and susceptibility of colorectal cancer: A meta-analysis.

Studies on the relationship between ABCB1 3435C>T polymorphism (rs1045642) and colorectal cancer (CRC)susceptibility have yielded inconclusive results. To clarify this issue, we undertook a meta-analysis to investigate the relationship between rs1045642 and CRC risk.Three electronic scientific publication databases (Cochrane Library, Pubmed, Embase) were screened using specific search terms. Relevant literature was identified using literature traceability methods. Selected publications were evaluated according to the inclusion and exclusion criteria. Effect size information (odds ratio and the corresponding 95% confidence interval [CI]) was obtained following quality assessment and data extraction from the included publications, and a meta-analysis conducted. Statistical analysis was performed with the Stata sofz (Version 13.0) software.Overall, 17 case-control studies involving 7129 CRC patients and 7710 healthy control subjects satisfied the criteria for inclusion in the meta-analysis. There was no significant association between ABCB1 3435C>T polymorphism and CRC risk in any of the genetic models. In the CC versus CT model (I = 20.9%, Pheterogeneity = .276), CC versus CT + TT model (I = 45.6%, Pheterogeneity = .102) and CT versus CC + TT model (I = 17.8%, Pheterogeneity = .298) analyses, between-study heterogeneities were detected as significant in Asian populations. In the CT versus TT model (I = 24%, Pheterogeneity = .254) and CC + CT versus TT model (I = 0, Pheterogeneity = .55), between-study heterogeneities were found to be significant in groups of different populations.The meta-analysis described here suggests that the ABCB1 3435C>T polymorphism is not related to CRC susceptibility.

Sp1-mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2-overexpressing breast cancer.

Human epidermal growth factor receptor 2 (HER2/erbB2) is a key driver and therapeutic target for breast cancer. The treatment of HER2-positive breast cancer remains a clinical challenge largely due to the limited understanding of HER2-driving oncogenic signaling and the frequent resistance to simply HER2-targeted therapy. Here, we show that the histone deacetylase inhibitor, trichostatin A (TSA), suppresses HER2-overexpressing breast cancer via upregulation of miR-146a and the resultant repression of its oncogenic targets, interleukin-1 receptor-associated kinase 1 and the chemokine receptor CXCR4. Mechanistically, histone H3K56 acetylation and deacetylation on the MIR146A promoter are catalyzed respectively by the acetyltransferase p300 and histone deacetylase 1 (HDAC1), both of which are recruited to the genomic loci by the transcription factor specificity protein 1 (Sp1). HER2 signaling phosphorylates Sp1 and induces its predominant association with HDAC1, but not p300, leading to histone hypoacetylation and silencing of MIR146A. In addition, the death receptor Fas is similarly downregulated by the aforementioned epigenetic paradigm, indicating its wide involvement in impairing tumor suppressor gene expression. Consequently, TSA synergizes with lapatinib, a tyrosine kinase inhibitor of HER2, to suppress breast cancer in vitro and in rodent models. These findings demonstrate a novel mechanism of HER2-driven carcinogenesis and suggest the applicability of combined HER2 and HDAC targeting in breast cancer therapy.

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor.

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1ß (HRG1ß) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1ß-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1ß-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

High expression of CREPT promotes tumor growth and is correlated with poor prognosis in colorectal cancer.

CREPT (cell cycle-related and expression elevated protein in tumor) is highly expressed in many kinds of cancer, and has been shown to be prognostic in certain cancers. However, the clinical significance of CREPT in colorectal cancer (CRC) has not been sufficiently investigated. In this study, we examined the CREPT expression in 225 clinical CRC tissues and paired adjacent normal tissues, and analyzed the correlation between CREPT expression and other clinicopathological features. We also evaluated the biological function of CREPT both in vitro and in vivo using knockdown or overexpressing CRC cells. Our results showed that CREPT expressed in 175 of 225 (77.8%) CRC patients and the CREPT expression was significantly associated with tumor differentiation (P = 0.000), Dukes' stages (P = 0.013) and metastasis (P = 0.038). Patients with high CREPT expression tended to have shorter survival time. Multivariate analysis showed that positive CREPT expression can be used as an independent predictor for CRC prognosis. CREPT knockdown cells showed inhibited cell proliferation and arrested cell cycle, while CREPT overexpressing cells showed increased proliferation and promoted cell cycle. In addition, CREPT overexpression significantly promoted tumor growth in vivo. Mechanism study showed that CREPT may regulate cell proliferation and cell cycle through the regulation on cyclin D3, CDK4 and CDK6.