Programmed Death-ligand 1 Blockade Research Articles

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this. Objectives: We studied the tolerogenic role of PD-L1+ dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD. Methods: We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively. Measurement and main results: A total of 83 participants were enrolled (normal, n = 29; COPD, n = 54). A reduced PD-L1+ conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, p = 0.03). The decrease in the PD-L1+ cDC1 ratio was associated with a rapid decline in COPD (p = 0.02) and correlated with the CD4+ T cells (r = −0.33, p = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of PD-L1 and CD4, but not CD8 were negatively correlated from PBMC in COPD patients (r = −0.43, p = 0.002). Functionally, the PD-L1 blockade enhanced CD4+ T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, p = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, p = 0.03) and CD3/elastin (148 ± 64.9, p = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of RORC, a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = −0.33, p = 0.02). Conclusions: Circulating PD-L1+ cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation.

Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade. The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control. PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

Neutrophils Expressing Programmed Death-Ligand 1 Play an Indispensable Role in Effective Bacterial Elimination and Resolving Inflammation in Methicillin-Resistant Staphylococcus aureus Infection.

Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types and known for its suppressive effect on T cells through its interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophils has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. The administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function, suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by their increased plasma alanine transaminase (ALT) levels and frequencies of inflammatory leukocytes in the liver, implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for the enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities, assisting in a smooth transition into the resolution phase in MRSA infection.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

Association analysis of FXYD5 with prognosis and immunological characteristics across pan-cancer

BackgroundThe FXYD domain-containing ion transport regulator 5 (FXYD5) gene is a cancer promoter. However, evidence for an association between FXYD5 and various types of cancer is still lacking. Using multi-omics bioinformatics, our study aimed to reveal the expression distribution, prognostic value, immune infiltration correlation, and molecular functions of FXYD5. MethodsUsing pan-cancer multi-omics data (including The Cancer Genome Atlas, PrognoScan, Gene Expression Profiling Interactive Analysis, cBioPortal, Gene Expression Omnibus, TIMER and scTIME Portal), we assessed the differences in the expression and prognostic value of FXYD5 in malignant tumors. Furthermore, at the single-cell level, we analyze the expression distribution of FXYD5 across different cell types within the tumor microenvironment, and its relationship with the immune microenvironment. Finally, focusing on ovarian cancer, we conducted preliminary validation of the above findings using cell and molecular biology techniques. ResultsOur results indicated that FXYD5 was up-regulated in various tumor types and was positively associated with tumor progression. We also revealed that FXYD5 was ubiquitously expressed in microenvironmental cells at the single-cell level, and its upregulation was associated with enhanced immune infiltration, cancer-associated fibroblast infiltration, and dysfunction of tumor-infiltrating cytotoxic T lymphocyte. Additionally, its expression was positively correlated with immune checkpoint genes, DNA mismatch repair genes, MSI (microsatellite instability) and TMB (tumor mutational burden) across various cancers. Its higher expression in cytotoxic T lymphocytes attenuated its ability to predict patient survival with PD-L1 (programmed death-ligand 1) blockade therapy, and FXYD5 was found to be a potential regulator of tumor immune escape and resistance to cancer immunotherapies. Based on GSEA (gene set enrichment analysis) and experimental verification, FXYD5 activated TGF‐β/SMAD signaling and drove EMT (epithelial-mesenchymal transition) to promote ovarian cancer progression. ConclusionIn summary, our study revealed that FXYD5-TGFβ axis may coregulate the interaction between tumors, CAFs (carcinoma-associated fibroblasts) and immune cells to reshape the tumor immune microenvironment and promote tumorigenesis and tumor progression. Thus, FXYD5 could be used as an immune-related biomarker for diagnosing and predicting the prognosis of multiple cancer types. Therefore, our findings suggest that targeting FXYD5 in TME (tumor microenvironment) may be a promising therapeutic strategy.

Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy

The cellular source of positive signals that reinvigorate Tcells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ Tcell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ Tcells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ Tcell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.

Immune Checkpoint Inhibitors: A Narrative Review on PD-1/PD-L1 Blockade Mechanism, Efficacy, and Safety Profile in Treating Malignancy.

Checkpoint inhibitors have been implicated in the treatment of several cancers due to their ability to exploit the immune system's regulatory pathways. This article serves to emphasize the importance of these immunotherapeutic agents and provide further insight into their mechanisms, efficacies, and safety profiles. The main agents in question include programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Several literature sources were found to assess the use of these inhibitors in cancers involving the lung, breast, and skin. Several peer-reviewed systematic reviews and the outcomes of clinical trials are combined within this article to support the use and further investigation of these agents in treating neoplasms. Further research into these forms of therapy underscores the revolutionary advancement of oncological interventions, which is important given the rising incidence of neoplasms within populations.

Metabolic Tumor Volume as Significant Predictor for Chemotherapy Containing PD-L1 Blocker in Extensive Stage Small Cell Lung Cancer.

Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.

GABA/baclofen stabilizes PD-L1 and enhances immunotherapy of breast cancer

The programmed death-ligand 1 (PD-L1) on the surface of tumor cells binds to the receptor programmed cell death protein 1 (PD-1) on effector T cells, thereby inhibiting the anti-tumor immune response. Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has been approved for the treatment of human cancers with lasting clinical benefit. However, many cancer patients did not respond to anti-PD-1/PD-L1 antibody blocking therapy or drugs targeting PD-1/PD-L1. Recent studies have shown that the response to PD-1/PD-L1 blockade may be related to the PD-L1 abundance of tumor cells. Therefore, it is of crucial significance to find drugs to regulate the expression of PD-L1, which can provide new strategies to improve the response rate and efficacy of PD-1/PD-L1 blocking in cancer treatment. Here, we found that GABA and baclofen, upregulates the protein level of PD-L1 by reducing the mRNA and protein levels of STUB1, a E3 ubiquitin ligase, thereby decreasing the interaction between STUB1 and PD-L1, and ultimately stabilizing PD-L1. Notably, GABA and baclofen did not affect cell proliferation in vitro, while in the treatment of breast cancer in mice, the therapeutic effect of baclofen combined with anti-PD-L1 antibody is significantly better than that of using anti-PD-L1 antibody alone by stimulating tumor infiltration of CD8+ T cells and antitumor immunity. Taken together, we unveiled a previously unappreciated role of GABA/baclofen in stabilizing PD-L1 and enhancing the immunotherapy of breast cancer.

Targeting KDM4 family epigenetically triggers antitumour immunity via enhancing tumour-intrinsic innate sensing and immunogenicity.

Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.

Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity

BackgroundAntineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer...

Ginsenoside Rh2 augmented anti-PD-L1 immunotherapy by reinvigorating CD8+ T cells via increasing intratumoral CXCL10

Profiting from the sustained clinical improvement and prolonged patient survival, immune checkpoint blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has emerged as a revolutionary cancer therapy approach. However, the anti-PD-1/PD-L1 antibodies only achieve a clinical response rate of approximately 20%. Herein, we identified a novel combination strategy that Chinese medicine ginseng-derived ginsenoside Rh2 (Rh2) markedly improved the anti-cancer efficacy of anti-PD-L1 antibody in mice bearing MC38 tumor. Rh2 combined with anti-PD-L1 antibody (combo treatment) further triggered the infiltration, proliferation and activation of CD8+ T cells in the tumor microenvironment (TME). Depletion of CD8+ T cells by mouse CD8 blocking antibody abolished the anti-cancer effect of combo treatment totally. Mechanistically, combo treatment further increased the expression of CXCL10 through activating TBK1-IRF3 signaling pathway, explaining the increased infiltration of T cells. Employing anti- CXC chemokine receptor 3 (CXCR3) blocking antibody prevented the T cells infiltration and abolished the anti-cancer effect of combo treatment. Meanwhile, combo treatment increased the percentage of M1-like macrophages and raised the ratio of M1/M2 macrophages in TME. By comparing the anti-cancer effect of combo treatment among MC38, CT26 and 4T1 tumors, resident T cells were considered as a prerequisite for the effectiveness of combo treatment. These findings demonstrated that Rh2 potentiated the anti-cancer effect of PD-L1 blockade via promoting the T cells infiltration and activation, which shed a new light on the combination strategy to enhance anti-PD-L1 immunotherapy by using natural product Rh2.

PD-L1 Blockade Improves Survival in Sepsis by Reversing Monocyte Dysfunction and Immune Disorder

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 −) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction.

USP2 promotes tumor immune evasion via deubiquitination and stabilization of PD-L1.

The abnormal upregulation of programmed death ligand-1 (PD-L1) on tumor cells impedes T-cell mediated cytotoxicity through PD-1 engagement, and further exploring the mechanisms regulation of PD-L1 in cancers may enhance the clinical efficacy of PD-L1 blockade. Here, using single-guide RNAs (sgRNAs) screening system, we identify ubiquitin-specific processing protease 2 (USP2) as a novel regulator of PD-L1 stabilization for tumor immune evasion. USP2 directly interacts with and increases PD-L1 abundance in colorectal and prostate cancer cells. Our results show that Thr288, Arg292 and Asp293 at USP2 control its binding to PD-L1 through deconjugating the K48-linked polyubiquitination at lysine 270 of PD-L1. Depletion of USP2 causes endoplasmic reticulum (ER)-associated degradation of PD-L1, thus attenuates PD-L1/PD-1 interaction and sensitizes cancer cells to T cell-mediated killing. Meanwhile, USP2 ablation-induced PD-L1 clearance enhances antitumor immunity in mice via increasing CD8+ T cells infiltration and reducing immunosuppressive infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), whereas PD-L1 overexpression reverses the tumor growth suppression by USP2 silencing. USP2-depletion combination with anti-PD-1 also exhibits a synergistic anti-tumor effect. Furthermore, analysis of clinical tissue samples indicates that USP2 is positively associated with PD-L1 expression in cancer. Collectively, our data reveal a crucial roleof USP2 for controlling PD-L1 stabilization in tumor cells, and highlight USP2 as a potential therapeutic target for cancer immunotherapy.

Correlation of Lung Immune Prognostic Index With Efficacy of PD-1/PD-L1 Inhibitor Combined With Chemotherapy and Prognosis in Patients With Advanced Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a devastating but universal class of lung carcinoma with an unfavorable prognosis. This paper mainly investigated the correlation between lung immune prognostic index (LIPI) score and combined treatment of immune checkpoint inhibitor and chemotherapy (CHT) in patients with advanced NSCLC. Totally, 301 advanced NSCLC patients with programmed death-ligand 1 (PD-L1) expression ≥1% were assigned into good LIPI group (N=113), intermediate LIPI group (N=101), and poor LIPI group (N=87) based on LIPI scoring system, followed by treatment of CHT plus programmed cell death-1 (PD-1)/PD-L1 inhibitor. The differences in clinical parameters between subgroups of NSCLC patients were analyzed by χ 2 test, 1-way analysis of variance, and Kruskal-Wallis H test. All patients were followed up until June 30, 2022, and objective response rate, disease control rate, progression-free survival (PFS), and overall survival (OS) were recorded. The independent associations of LIPI score with PFS and OS were assessed via the Cox regression model. There were evident differences in clinical stage and lymphocyte among the 3 subgroups of NSCLC patients. The efficacy of PD-1/PD-L1 inhibitor combined with CHT was better in patients with good LIPI score, manifested by higher objective response rate and disease control rate. Moreover, LIPI score was an independent factor influencing PFS and OS in patients with advanced NSCLC, with longer PFS and OS in patients with good LIPI score. LIPI score has a predictive value for combination therapy of PD-1/PD-L1 blockade and CHT in advanced NSCLC patients.

IFN-γ–dependent interactions between tissue-intrinsic γδ T cells and tissue-infiltrating CD8 T cells limit allergic contact dermatitis

Elicitation of allergic contact dermatitis (ACD), an inflammatory type 4 hypersensitivity disease, induces skin infiltration by polyclonal effector CD8 αβ T cells and precursors of tissue-resident memory T (TRM) cells. Because TRM have long-term potential to contribute to body-surface immunoprotection and immunopathology, their local regulation needs a fuller understanding. We sought to investigate how TRM-cell maturation might be influenced by innate-like T cells pre-existing within many epithelia. This study examined CD8+ TRM-cell maturation following hapten-induced ACD in wild-type mice and in strains harboring altered compartments of dendritic intraepidermal γδ T cells (DETCs), a prototypic tissue-intrinsic, innate-like T-cell compartment that reportedly regulates ACD, but by no elucidated mechanism. In addition to eliciting CD8 TRM, ACD induced DETC activation and an intimate coregulatory association of the 2 cell types. This depended on DETC sensing IFN-γ produced by CD8 cells and involved programmed death-ligand 1 (PD-L1). Thus, in mice lacking DETC or lacking IFN-γ receptor solely on γδ cells, ACD-elicited CD8 T cells showed enhanced proliferative and effector potentials and reduced motility, collectively associated with exaggerated ACD pathology. Comparable dysregulation was elicited by PD-L1 blockade invitro, and IFN-γ-regulated PD-L1 expression was a trait of human skin-homing and intraepithelial γδ T cells. The size and quality of the tissue-infiltrating CD8 T-cell response during ACD can be profoundly regulated by local innate-like T cells responding to IFN-γ and involving PD-L1. Thus, interindividual and tissue-specific variations in tissue-intrinsic lymphocytes may influence responses to allergens and other challenges and may underpin inflammatory pathologies such as those repeatedly observed in γδ T-cell-deficient settings.

Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.

STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC

IntroductionConflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been reported that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 phenotype rather than mutation may better stratify ICB outcomes. MethodsSelected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11-deficient [-def] or -proficient [-prof]). We analyzed in-house and Genentech/Roche’s data of three randomized trials of programmed cell death protein-1 or programmed death-ligand 1 (PD-L1) inhibition in NSCLC (ORIENT-11, n = 171; OAK, n = 699; POPLAR, n = 192) and The Cancer Genome Atlas–NSCLC cohort. ResultsTissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy were lost or reversed in STK11-def tumors (hazard ratios for death, 95% confidence interval: OAK [0.97, 0.69–1.35]; POPLAR [1.61, 0.88–2.97]; ORIENT-11 [1.07, 0.50–2.29]), while remaining in STK11-prof tumors (hazard ratios for death, 95% confidence interval: OAK [0.81, 0.66–0.99]; POPLAR [0.66, 0.46–0.95]; ORIENT-11 [0.59, 0.37–0.92]). In tumors differentially classified by phenotype and mutation status, STK11–wild-type/def tumors had significantly worse ICB outcomes than STK11-mutated (STK11-MUT)/prof tumors (p < 0.05). The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/interferon-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-def tumors rather than those with STK11-MUT tumors. Surprisingly, whereas high CD8+ T-cell infiltration was significantly associated with prolonged survival with ICB in STK11-prof tumors (p < 0.05 for 3 trials), it predicted an opposite trend toward worse ICB outcomes in STK11-def tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T-cell dysfunction, which might not be reversed by programmed cell death protein 1 or PD-L1 blockade. ConclusionsSTK11 phenotype rather than mutation status can accurately identify patients with ICB-refractory NSCLC and reflect immune suppression. It can help refine stratification algorithms for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.

CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.

Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.

Cinchonine exerts anti-tumor and immunotherapy sensitizing effects in lung cancer by impairing autophagic-lysosomal degradation

Currently, there are several treatments approaches available for lung cancer; however, patients who develop drug resistance or have poor survival rates urgently require new therapeutic strategies for lung cancer. In autophagy, damaged proteins or organelles are enclosed within autophagic vesicles with a bilayer membrane structure and transported to the lysosomes for degradation and recirculation. Autophagy is a crucial pathway involved in the clearance of reactive oxygen species (ROS) and damaged mitochondria. Meanwhile, inhibiting autophagy is a promising strategy for cancer treatment. In this study, we found for the first time that Cinchonine (Cin) can act as an autophagy suppressor and exert anti-tumor effects. Cin significantly inhibited the proliferation, migration, and invasion of cancer cells in vitro and the tumor growth and metastasis in vivo, without obvious toxic effects. We found that Cin suppressed the autophagic process by blocking autophagosome degradation through the inhibition of the maturation of lysosomal hydrolases. Cin-mediated autophagy inhibition resulted in the elevated ROS level and the accumulation of damaged mitochondria, which in turn promoted apoptosis. N-acetylcysteine, a potential ROS scavenger, significantly suppressed Cin-induced apoptosis. Additionally, Cin upregulated programmed death-ligand 1 (PD-L1) expression in lung cancer cells by inhibiting autophagy. Compared with monotherapy and control group, the combined administration of anti-PD-L1 antibody and Cin significantly reduced tumor growth. These results suggest that Cin exerts anti-tumor effects by inhibiting autophagy, and that the combination of Cin and PD-L1 blockade has synergistic anti-tumor effects. The data demonstrates the significant clinical potential of Cin in lung cancer treatment.