Programmed Cell Death Ligand-1 Axis Research Articles

Tumor cells inhibit the activation of ILC2s through up-regulating PD-1 expression

Objective Up-regulating programmed cell death ligand-1(PD-L1) expressed on tumor cells and tumor-infiltrating myeloid cells interacting with up-regulated programmed cell death-1 (PD-1) expressed on tumor-infiltrating lymphoid cells greatly hinder their tumor-inhibiting effect. It is necessary to explore the deep mechanism of this negative effect, so as to find the potential methods to improve the immunotherapy efficiency. Methods and Results In this study, we found that the PD-1 expression in lung cancer-infiltrating type II innate lymphoid cells (ILC2s) was highly up-regulated, which greatly restrained the activation and function of ILC2s. Furthermore, anti-PD-1 could restore the inhibition and effective cytokine secretion of ILC2s when co-cultured with tumor cells. In vivo studies proved that anti-PD-1 treatment promoted the activation of tumor-infiltrating ILC2s and inhibited the tumor growth of LLC-bearing nude mice. Discussion Our studies demonstrate a new PD-1/PD-L1 axis regulating mechanism on innate immune cells, which provide a useful direction to ILC2s-based immunotherapy to cancer diseases.

PD-1/PD-L1 pathway: Current research in breast cancer.

Immunotherapy has shown encouraging outcomes in breast cancer (BC) treatment in recent years. The programmed cell death ligand 1 (PD-L1) transmembrane protein is suggested to function as a co-inhibitory factor in the immune response, where it collaborates with programmed cell death protein 1 (PD-1) to stimulate apoptosis, suppress cytokine release from PD-1 positive cells, and limit the growth of PD-1 positive cells. Furthermore, in many malignancies, PD-L1 reduces the immune system's response to neoplastic cells. These observations suggest that the PD-1/PD-L1 axis plays a vital role in cancer therapy and the regulation of cancer immune escape mechanisms. This review aimed to provide an overview of the functions of PD-1 and PD-L1 in BC cancer therapy. This research design is a literature review. The style is a traditional review on topics or variables relating to the PD-1/PD-L1 pathway. A literature search was carried out using three online databases. The search using the keywords yielded a total of 248 studies. Each result was filtered again according to the inclusion and exclusion criteria, resulting in a final total of 4 studies to be included in the literature review. The combination of PD-1/PD-L1 is essential for many malignancies. According to the evidence presented, this combination presents both an opportunity and a challenge in cancer treatment. Since many solid cancers, especially BC, express high levels of PD-1/PD-L1, cancer treatment mainly involves targeted therapies.

Circ_0027791 contributes to the growth and immune evasion of hepatocellular carcinoma via the miR-496/programmed cell death ligand 1 axis in an m6A-dependent manner.

Emerging evidence indicates the critical roles of circular RNAs in the development of multiple cancers, containing hepatocellular carcinoma (HCC). Herein, our present research reported the biological function and mechanism of circ_0027791 in HCC progression. Circ_0027791, microRNA-496 (miR-496), programmed cell death ligand 1 (PDL1), and methyltransferase-like 3 (METTL3) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, proliferation, invasion, and sphere formation ability were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, transwell, and sphere formation assays. Macrophage polarization was detected using flow cytometry assay. To understand the role of circ_0027791 during the immune escape, HCC cells were cocultured with peripheral blood mononuclear cells or cytokine-induced killer (CIK) cells in vitro. A xenograft mouse model was applied to assess the function of circ_0027791 in vivo. After prediction using circinteractome and miRDB, the binding between miR-496 and circ_0027791 or PDL1 was validated based on a dual-luciferase reporter assay. Interaction between METTL3 and circ_0027791 was determined using methylated RNA immunoprecipitation (MeRIP)-qPCR, RIP-qPCR, and RNA pull-down assays. Circ_0027791, PDL1, and METTL3 expression were upregulated, and miR-496 was decreased in HCC patients and cells. Moreover, circ_0027791 knockdown might repress proliferation, invasion, sphere formation, M2 macrophage polarization, and antitumor immune response. Circ_0027791 knockdown repressed HCC tumor growth in vivo. In mechanism, circ_0027791 functioned as a sponge for miR-496 to increase PDL1 expression. In addition, METTL3 mediated the m6A methylation of circ_0027791 and stabilized its expression. METTL3-induced circ_0027791 facilitated HCC cell progression partly regulating the miR-496/PDL1 axis, which provided a new prognostic and therapeutic marker for HCC.

Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of Tcells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating Tcell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor Tcell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.

Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.

Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with programmed cell death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction with PD-1, which provides more challenges for the discovery of PD-L1 inhibitors. Herein, we report the discovery of novel PD-L1 inhibitors using the fragment coupling strategy. Among them, B9 was found to inhibit the PD-1/PD-L1 interaction with the best IC50 value of 1.8 ± 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, B9 promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, B9 displayed high in vivo antitumor efficacy in the CT26 mouse model and activated the immune microenvironment and induced PD-L1 degradation of PD-L1 in the tumor. These results show that B9 is a promising lead PD-L1 inhibitor through the blockade of PD-1/PD-L1 interaction and functional inhibition of the PD-L1 signal pathway.

Synergetic regulation of cancer cells and exhausted T cells to fight cold tumors with a fluorinated EGCG-based nanocomplex.

Immune therapy that targets PD-L1 (programmed cell death-ligand 1) is attractive to augment immune response by breaking the programmed cell death-1 (PD-1)/PD-L1 axis. However, T cell exhaustion associated with insufficient T cells infiltration may diminish the efficacy of cancer therapy. Here, we report a novel delivery system of FEGCG/FPEI@siTOX composed of fluorinated EGCG (FEGCG) and fluorinated polyethyleneimine (FPEI) for delivery of small interfering RNA anti-TOX (thymus high mobility group box protein, TOX) to treat tumor and metastasis. In this way, the reduction in PD-L1 expression by FEGCG can promote T-cell function, while inhibition of TOX expression with siTOX can alleviate T-cell exhaustion. FPEI are designed to deliver siRNA with high efficiency and low toxicity compared to classical PEI. Integrating FEGCG, FPEI and siTOX into such a novel system resulted in excellent anti-tumor and antimetastatic effects. It is a promising delivery system and potential strategy for the treatment of "cold" tumors.

Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis

BackgroundMediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking.MethodsProgrammed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated.ResultsWe analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics.ConclusionsMediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

KSCBi005-A-8(hiPSC-PD-L1KO), a PD-L1 knockout human induced pluripotent stem cell line for demonstrating the role of the PD-1/PD-L1 axis

Programmed Cell Death Ligand 1 (PD-L1) is a trans-membrane protein that attenuates the host immune response to tumor cells. PD-L1 ligand on the surface of the cancer binds to PD-1 transmembrane receptors on T cells and exhausts T cells function. Using CRISPR-Cas9 genome editing, we generated biallelic PD-L1 mutants in human induced pluripotent stem cells (hiPSCs). The PD-L1 homozygous-knockout hiPSCs retained their normal morphology, gene expression, and in vivo differentiation potential.

Novel 4-Arylindolines Containing a Pyrido[3,2-d]pyrimidine Moiety as the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction Inhibitors for Tumor Immunotherapy.

A series of pyrido[3,2-d]pyrimidine-containing 4-arylindolines were identified as potent inhibitors of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by structural optimization of a 4-arylindoline precursor reported previously. Among them, compound N11 was the most promising inhibitor, showing an IC50 value of 6.3 nM against the PD-1/PD-L1 interaction at the biochemical level. In in vitro T-cell tumor co-culture models, N11 significantly promoted T-cell proliferation, activation, and infiltration into tumor spheres, demonstrating that it possessed excellent immunomodulatory activity. In addition, N11 exhibited favorable in vivo antitumor activity in an LLC/PD-L1 tumor-bearing mouse model. Flow cytometry analysis verified that the in vivo antitumor efficacy of N11 was dependent on the activation of the immune microenvironment. These findings suggest that N11 can serve as a new starting point for the future development of small-molecule antitumor immunomodulators targeting the PD-1/PD-L1 axis.

Circular RNA hsa_circ_0005239 contributes to hepatocellular carcinoma cell migration, invasion, and angiogenesis by targeting the miR-34a-5p/PD-L1 axis.

Circular RNAs (circRNAs) may be involved in tumorigenesis. Recently, the role of circRNAs in hepatocellular carcinoma (HCC) has drawn wide attention. Herein, we aimed to explore the regulation and function of hsa_circ_0005239 in the malignant biological behavior and angiogenesis of HCC, as well as the link between hsa_circ_0005239 and programmed cell death ligand 1 (PD-L1) in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) assays revealed that hsa_circ_0005239 was upregulated in HCC tumor samples and cell lines. Furthermore, a series of in vitro and in vivo assays explored the effects of hsa_circ_0005239 on biological processes involved in the development of HCC. Knockdown of hsa_circ_0005239 significantly inhibited cell migration, cell invasion, and angiogenesis in HCC, while overexpression showed the opposite effect. In the in vivo assays, hsa_circ_0005239 downregulation suppressed the growth of xenograft tumors in nude mice, which supported that hsa_circ_0005239 is a tumor promoter in HCC. Mechanistically, hsa_circ_0005239 binds to miR-34a-5p and functions as a competing endogenous RNA to modulate the expression of PD-L1. Further experiments revealed that the hsa_circ_0005239/PD-L1 axis regulates the malignant phenotypes of HCC cells through the phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. These results revealed the role of hsa_circ_0005239 and the hsa_circ_0005239/miR-34a-5p/PD-L1 axis in HCC, providing a potential diagnostic biomarker and therapeutic target for HCC.

Checkmate with checkpoint inhibitors: New paradigm in immunotherapy

Cancer immunotherapy is a form of biotherapy (also called biological response modifier therapy) that refers to a broad array of anti-cancer therapies targeted to activate and trigger the body’s immune system against cancer. This includes targeted antibodies to specific cell surface entities on cancer cells, anti-cancer vaccines like vaccines against HPV in cervical cancer, cytolytic virus, adoptive cell transfer, biologicals like cytokines and other small molecular agents, and the most explored immune checkpoint inhibitors. Immunotherapies use immune modulatory materials from the same organism to fight disease, while some immunotherapy treatments use genetic engineering-based gene editing approaches to enhance the host immune system in an effort to eradicate the cancer cells and boost its cancer-fighting capabilities. Used in combination with surgery, chemotherapy, and radiotherapy, cancer immunotherapy improves their overall effectiveness. WHAT IS AN IMMUNE CHECKPOINT T cell activation involves the engagement of a number of signaling cascades, originating from the interaction between T cell receptors (TCR) with antigen-presenting cells (APC) that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. TCR alone is not sufficient to generate an adequate response. It needs the participation of coreceptors. Primary T cell activation involves the integration of three distinct signals (1) antigen recognition in the presence of APC, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. To make sure that these activated T cells do not cross-react with self-antigens, these are rendered inactive by immune checkpoints. PDL on T cells and PDL1 on host cells engage in bringing about this. Programmed Cell Death Protein 1 (PD-1) inhibits immune responses by fostering a state of self-tolerance. This is achieved by activating apoptosis, anergy, and avoidance of antigen-specific T cells. The functional counterpart of PD-1, the Programmed Cell Death Ligand 1 (PD-L1), is a trans-membrane protein that acts as a coinhibitory immune response factor. This is what the cancer cells hijack for their survival. PD-L1 expressed on cancer cells attenuates the host T cell response transmitting negative signals. Therefore, the PD-1/PD-L1 axis is the main driver of cancer immune evasion, which needs serious attention. WHAT IS IMMUNE CHECKPOINT INHIBITORS These classes of molecules are designed to block the cross-talks between cancer cells expressing PD-L1 with T cells expressing PD-1 receptors. When the interaction is blocked, inhibitory influence on T-cells is circumvented, and an attack may be launched. Checkpoint inhibitors are used in cancer immunotherapy, including a wide range of cancers, such as melanoma, skin cancer, and lung cancer. Different drug classes block checkpoint proteins like CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. Commercially checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo), and atezolizumab (Tecentriq). RAYS OF HOPE AND CAUTION Because checkpoint inhibitors stimulate the immune system and are immunomodulatory, their usage has significantly improved cancer treatment and management, extending the life span for numerous patients. However, we need to be cautious as they may cause immune cells to attack healthy cells, causing side effects such as fatigue, nausea, high fever, flu-like symptoms, and inflammation.

Hsa_circ_0003528 promotes cell malignant transformation and immune escape via increasing oncogene PDL1 through sponging miR‐511‐3p in non‐small cell lung cancer

Accumulating evidence suggests that circular RNAs (circRNAs) play important regulatory roles in non-small cell lung cancer (NSCLC). At present, we aimed to explore the regulatory role of has_circ_0003528 (circ_0003528) in NSCLC. Alterations of circ_0003528 expression in NSCLC samples and cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Impacts of circ_0003528 on NSCLC cell malignant transformation were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell invasion, and tube formation assays. Epithelial-mesenchymal transition (EMT)-related markers were detected with western blotting. Pro-inflammatory cytokines were detected by Enzyme-linked immunosorbent assay (ELISA). The regulation mechanism of circ_0003528 was verified by dual-luciferase reporter and RNA pull-down assays. The tumorigenesis role of circ_0003528 was verified by animal experiments. Higher levels of circ_0003528 were obtained in NSCLC samples and cell lines, and patients with high circ_0003528 expression had a worse prognosis. Silence of circ_0003528 decreased xenograft growth in mouse models and induced cell apoptosis and repressed cell viability, proliferation, invasion, EMT, angiogenesis, and immune escape in NSCLC cells in vitro. Mechanistically, circ_0003528 controlled programmed cell death ligand 1 (PDL1) expression through interaction with miR-511-3p. The inhibiting impacts of circ_0003528 knockdown on NSCLC cell malignant transformation and immune escape were weakened after miR-511-3p silencing. Moreover, PDL1 overexpression partially counteracted miR-511-3p upregulation-mediated suppression on NSCLC cell malignant transformation and immune escape. Circ_0003528 facilitated NSCLC cell malignant transformation and immune escape through regulation of the miR-511-3p/PDL1 axis, highlighting the oncogenic role of circ_0003528 in NSCLC.

Reversing Immune Suppression and Potentiating Photothermal Immunotherapy via Bispecific Immune Checkpoint Inhibitor Loaded Hollow Polydopamine Nanospheres.

Despite the great achievements of immune checkpoint blockade (ICB) therapy on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, ICB monotherapy still faces obstacles in eradicating solid tumors due to the lack of tumor-associated antigens or tumor-specific cytotoxicity. Photothermal therapy (PTT) is a potential therapeutic modality because it can noninvasively kill tumor cells by thermal ablation and generate both tumor-specific cytotoxicity and immunogenicity, which holds great feasibility to improve the efficiency of ICB by providing complementary immunomodulation. Except for the PD-1/PD-L1 axis, the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) pathway has been considered as a novel strategy of tumor cells to evade the surveillance of macrophages and inactivate the immune response of PD-L1 blockade therapy. Therefore, it is necessary to synergize the antitumor effect of dual-targeting PD-L1 and CD47. Although promising, the application of PD-L1/CD47 bispecific antibodies, especially in combination with PTT, remains a formidable problem, due to the low objective response, activity loss at relatively high temperature, or nonvisualization. Herein, instead of using antibodies, we use MK-8628 (MK) to down-regulate both PD-L1 and CD47 simultaneously through halting the active transcription of oncogene c-MYC, leading to elicitation of the immune response. The hollow polydopamine (HPDA) nanospheres are introduced as a biocompatible nanoplatform with high loading capacity and magnetic resonance imaging (MRI) ability to deliver MK and induce PTT (HPDA@MK). Compared to preinjection, HPDA@MK exhibits the strongest MRI signal at 6 h postintravenous injection to guide the precise combined treatment time. However, due to the local delivery and controlled release of inhibitors, HPDA@MK down-regulates c-MYC/PD-L1/CD47, promotes the activation and recruitment of cytotoxic T cells, regulates the M2 macrophages polarization in tumor sites, and especially boosts the combined therapeutic efficacy. Collectively, our work presents a simple but distinctive approach for c-MYC/PD-L1/CD47-targeted immunotherapy combined with PTT that may provide a desirable and feasible strategy for the treatment of other clinical solid tumors.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50=8.9nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50>5000mg/kg and showed significant invivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Disruption of RBMS3 suppresses PD-L1 and enhances antitumor immune activities and therapeutic effects of auranofin against triple-negative breast cancer

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction exerts a vital role in tumor-associated immune evasion. While strategies disrupting PD-1/PD-L1 axis have shown clinical benefits in various cancers, the limited response rate prompts us to investigate the complex mechanisms underlying the molecular regulation of PD-L1. Here, we identify the RNA binding protein RBMS3 as a crucial PD-L1 regulator in triple-negative breast cancer (TNBC). Correlation analysis shows that Rbms3 significantly correlates with immunosuppressive CD274, Rbms1, NT5E and ENTPD1. RBMS3 protein binds to CD274 mRNA specifically in TNBC cells to increase PD-L1 levels. Mechanistically, RBMS3 stabilizes CD274 mRNA by interacting with its 3′UTR, which represents as an intrinsic cancer cell mechanism for driving PL-D1 upregulation in TNBC. RBMS3 depletion not only destabilizes the mRNA stability and protein expression of PD-L1, but also suppresses the migratory abilities of TNBC MDA-MB-231 cells. Importantly, combination of RBMS3 ablation with auranofin (AUF), an FDA-approved thioredoxin reductase inhibitor, facilitates anti-tumor T-cell immunity in vivo and improves AUF-mediated anti-cancer effect. Taken together, our findings reveal RBMS3 as a key post-transcriptional regulator of PD-L1 and how they contribute to immune escape in TNBC, which could lead to novel combinatorial therapeutic strategies to enhance the efficacy of cancer immunotherapy.

114P Clinical interchangeability of programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays for the treatment of first-line (1L) non-small cell lung cancer (NSCLC) with cemiplimab

Multiple PD-L1 IHC assays have been developed independently targeting the PD-1/PD-L1 axis. The lack of harmonisation has created undue complexity for clinicians who use PD-L1 tests to guide treatment decisions. In this first-of-its-kind bridging study in 1L NSCLC, we demonstrate clinical agreement of two PD-L1 IHC assays using samples from pts treated with 1L cemiplimab in the phase III EMPOWER-Lung 1 study (NCT03088540).

Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy.

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

Yin Yang 1-stimulated long noncoding RNA bladder cancer-associated transcript 1 upregulation facilitates esophageal carcinoma progression via the microRNA-5590-3p/programmed cell death-ligand 1 pathway

ABSTRACT Esophageal carcinoma (EC) is a common gastrointestinal malignancy that poses a threat to public health worldwide. Long noncoding RNA (lncRNA) bladder cancer-associated transcript 1 (BLACAT1) exerts a tumorigenic role in several malignant tumors; nevertheless, its function in EC remains largely unknown. Besides, programmed cell death-ligand 1 (PD-L1), an oncogene in numerous human cancers, has been identified as a therapeutic target for EC. Therefore, we intended to explore the potential regulatory network involving BLACAT1 and PD-L1 in EC. In this study, we observed increased BLACAT1 and PD-L1 levels in EC tissues and EC cell lines. Moreover, YY1 could activate BLACAT1 transcription in EC cells (TE-1 and EC9706). In addition, in vitro and in vivo experiments demonstrated that BLACAT1 facilitated EC cell proliferation and metastasis and EC tumor growth. Also, the effects of BLACAT1 silencing on EC cell functions were partially reversed by PD-L1 overexpression. Besides, it was identified that BLACAT1 competed with PD-L1 to bind to miR-5590-3p in EC cells. Furthermore, miR-5590-3p suppression could abrogate the functional effects of BLACAT1 knockdown on EC cells; while PD-L1 silencing partly abolished the promoting effects of miR-5590-3p suppression on the biological functions of EC cells. To sum up, YY1-induced BLACAT1 accelerated EC progression via regulating the miR-5590-3p/PD-L1 axis.

CircFOXK2 enhances tumorigenesis and immune evasion in non-small cell lung cancer by miR-485-5p/PD-L1 axis.

Circular RNAs (circRNAs) serve a key role in lots of cancers. The outcomes of upregulated circular RNA forkhead box K2 (circFOXK2) on non-small cell lung cancer (NSCLC) persisted uncertainly. In this study, the role of circFOXK2 in NSCLC was inspected. The abundances of circFOXK2, microRNA-485-5p (miR-485-5p) and programmed cell death ligand-1 (PD-L1) were confirmed by quantitative real-time PCR and western blot. Cell counting kit-8 (CCK-8) assay and clonogenic assay were accomplished to conclude the proliferation of NSCLC cells. Wound healing and transwell assays were implemented to evaluate cell migration and invasion. Lactate dehydrogenase (LDH) cytotoxicity assay was enforced to quantify the cytotoxicity of CD8+ T cells. Flow cytometry assay was employed to detect apoptosis. Besides, the mice experiments were utilized for in vivo tumorigenesis analysis. Dual-luciferase reporter assay was carried out to reveal the associations between miR-485-5p and circFOXK2 or PD-L1. CircFOXK2 and PD-L1 levels were augmented in NSCLC. CircFOXK2 targeted miR-485-5p, which could bind to PD-L1. CircFOXK2 served a key role in NSCLC tumorigenesis and cytotoxicity of CD8+ T cells. MiR-485-5p inhibition or PD-L1 overexpression abolished the inhibitory effects of circFOXK2 lack on NSCLC tumorigenesis and cytotoxicity of CD8+ T cells. CircFOXK2 sponged miR-485-5p to stimulate PD-L1 and expedited NSCLC development.