PD-L1 Signaling Research Articles

Research Progress of PD 1/PD L1 Inhibitors in the Treatment of Urological Tumors.

Immune checkpoint inhibitors (ICIs) offer significant advantages for the treatment of urologic tumors, enhancing the immune function of anti-tumor T cells by inhibiting PD-1 and PDL1 binding. They have been shown to be well tolerated and remarkably effective in clinical practice, offering hope to many patients who are not well treated with conventional drugs. Clinical trials in recent years have shown that anti-PD-1 and PD-L1 antibodies have good efficacy and safety in the treatment of urologic tumors. These antibodies can be applied to a variety of urologic tumors, such as bladder cancer, renal cell carcinoma, and prostate cancer. They have been approved for the first-line treatment or as an option for follow-up therapy. By blocking the PD-1/PD-L1 signaling pathway, ICIs can release immune functions that are suppressed by tumor cells and enhance T-cell killing, thereby inhibiting tumor growth and metastasis. This therapeutic approach has achieved encouraging efficacy and improved survival for many patients. Although ICIs have shown remarkable results in the treatment of urologic tumors, some problems remain, such as drug resistance and adverse effects in some patients. Therefore, further studies remain important to optimize treatment strategies and improve clinical response in patients. In conclusion, PD-1/PD-L1 signaling pathway blockers have important research advances for the treatment of urologic tumors. Their emergence brings new hope for patients who have poor outcomes with traditional drug therapy and provides new options for immunotherapy of urologic tumors. The purpose of this article is to review the research progress of PD-1 and PD-L1 signaling pathway blockers in urologic tumors in recent years.

Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors

BackgroundAside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.MethodsWe genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies.ResultsWe show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i.ConclusionsOur data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.

Increased PD-1/PD-L1 Immune Checkpoint Expression Is Associated With Oral Squamous Cell Carcinoma in Never-Smokers and Never-Drinkers.

This study aimed to explore the disparities in PD-1 and PD-L1 expression among oral squamous cell carcinomas (OSCCs) in individuals categorized as never-smokers/never-drinkers versus smokers/drinkers. Immunohistochemical staining for PD-1 and PD-L1, along with PDCD1LG2/cen9 dual color probe analysis, was conducted on 130 OSCC specimens from both smoker/drinker and never-smoker/never-drinker cohorts. Associations between smoking/drinking status, clinicopathologic data, immunohistochemical antibody expression, fluorescence insitu hybridization, and survival outcomes were assessed. OSCC in never-smokers/never-drinkers exhibited significantly elevated PD-1 expression (p = 0.003), increased PD-L1-TPS expression (p = 0.044), and elevated PD-L1-CPS expression (p < 0.001). High PD-L1-ICS expression was more prevalent in never-smokers (p = 0.042). Moreover, never-smokers and never-drinkers demonstrated augmented PD-L1 gene copy numbers (p = 0.081 and p = 0.054, respectively). Increased PD-L1 gene copy number, particularly amplification, correlated with PD-L1-TPS (p = 0.039 and p < 0.001). Conversely, PD-L1 gene copy loss was associated with negative PD-L1-CPS (p = 0.023). Notably, positive PD-L1-CPS was significantly linked with improved overall survival (p = 0.023). OSCC arising in never-smokers/never-drinkers exhibit heightened PD-1/PD-L1 signaling, suggesting potential efficacy of immune checkpoint therapy in this subgroup of tumors.

QSOX1 facilitates dormant esophageal cancer stem cells to evade immune elimination via PD-L1 upregulation and CD8 T cell exclusion

Dormant cancer stem cells (DCSCs) exhibit characteristics of chemotherapy resistance and immune escape, and they are a crucial source of tumor recurrence and metastasis. However, the underlying mechanisms remain unrevealed. We demonstrate that enriched Gzmk+ CD8+ T cells within the niche of esophageal DCSCs restrict the outgrowth of tumor mass. Nonetheless, DCSCs can escape immune elimination by enhancing PD-L1 signaling, thereby maintaining immune equilibrium. Quiescent fibroblast-derived quiescin sulfhydryl oxidase 1 (QSOX1) promotes the expression of PD-L1 and its own expression in DCSCs by elevating the level of reactive oxygen species. Additionally, high QSOX1 in the dormant tumor niche contributes to the exclusion of CD8+ T cells. Conversely, blocking QSOX1 with Ebselen in combination with anti-PD-1 and chemotherapy can effectively eradicate residual DCSCs by reducing PD-L1 expression and promoting CD8+ T cell infiltration. Clinically, high expression of QSOX1 predicts a poor response to anti-PD-1 treatment in patients with esophageal cancer. Thus, our findings reveal a mechanism whereby QSOX1 promotes PD-L1 upregulation and T cell exclusion, facilitating the immune escape of DCSCs, and QSOX1 inhibition, combined with immunotherapy and chemotherapy, represents a promising therapeutic approach for eliminating DCSCs and preventing recurrence.

Downregulating LKB1 in bone marrow mesenchymal stem cells could inhibit CD4+ T cell proliferation via the PD-1/PD-L1 signaling pathway

BackgroundOur previous research has shown that LKB1 in amniotic mesenchymal stem cells (MSCs) serves as a vital regulator of regulatory T cell differentiation and T cell proliferation, which may have a similar role in bone marrow MSCs (BMMSCs). Therefore, we investigated the role of LKB1 in BMMSCs for regulating CD4+ T cell proliferation in the bone micro-environment of AML. MethodsRT-PCR was used to assessed LKB1 expression in BMMSCs derived from AML patients and healthy controls. Subsequently, LKB1 was knocked down in the BMMSCs line HS-5 (HS-5-LKB1KD). Co-cultures in vitro were established to analyze the effect of HS-5-LKB1KD on CD4+ T cell. Flow cytometry was employed to measure PD-L1 and CD4+ T cell proliferation levels. Western blot was utilized to detect related proteins. ResultsThe expression of LKB1 in BMMSCs derived from AML patients was decreased. Knockdown of LKB1 in HS-5 resulted in upregulation of PD-L1 expression. Co-culture of peripheral blood CD4+ T cell with HS-5-LKB1KD exhibited reduced CD4+ T cell proliferation compared to co-culture with HS-5-LKB1con. Furthermore, blocking PD-L1 in the co-culture conditions could restore the reduced CD4+ T cell proliferation. Additionally, it was found that upregulation of the Wnt signaling pathway-related proteins following LKB1 knockdown in HS-5, indicating that downregulating LKB1 could promote PD-L1 expression through activation of the Wnt signaling pathway. ConclusionsThe decreased expression of LKB1 in BMMSCs may activate the Wnt signaling pathway, leading to increased PD-L1 expression. This inhibited CD4+ T cell proliferation, which might lead to impaired anti-tumor immunity in AML patients and promote AML progression.

Unveiling the antitumor synergy between pazopanib and metformin on lung cancer through suppressing p-Akt/ NF-κB/ STAT3/ PD-L1 signal pathway

Pazopanib, an inhibitor of the VEGF receptor tyrosine kinase, has demonstrated significant antitumor effects in lung cancer. However, its application as a standard treatment for this type of cancer is limited by its drug resistance and toxicity. Metformin has the potential to combat lung cancer by modifying the tumor’s immune microenvironment.In this study, we investigated the potential antitumor effects and the associated underlying molecular mechanisms of the combination of pazopanib and metformin in lung cancer. In vitro studies were conducted using the A549 and H460 lung cancer cell lines, whereas urethane-induced lung cancer-bearing mice were used for in vivo assessments. The urethane-induced mice received oral administration of pazopanib (50 mg/kg) and/or metformin (250 mg/kg) for a duration of 21 days.The results indicated that the MTT assay demonstrated a combined cytotoxic effect of the pazopanib/metformin combination in H460 and A549 cells, as evidenced by CI and DRI analyses. The observed increase in annexin V levels and the corresponding increase in Caspase-3 activity strongly suggest that this combination induced apoptosis.Furthermore, the pazopanib/metformin combination significantly inhibited the p-Akt/NF-κB/IL-6/STAT3, HIF1α/VEGF, and TLR2/TGF-β/PD-L1 pathways while also increasing CD8 expression in vivo. Immunohistochemical analysis revealed that these antitumor mechanisms were manifested by the suppression of the proliferation marker Ki67. In conclusion, these findings revealed that metformin augments the antitumor efficacy of pazopanib in lung cancer by simultaneously targeting proliferative, angiogenic, and immunogenic signaling pathways, metformin enhances the antitumor effectiveness of pazopanib in lung cancer, making it a promising therapeutic option for lung cancer.

DNp73 enhances tumor progression and immune evasion in multiple myeloma by targeting the MYC and MYCN pathways.

Multiple myeloma (MM) is an incurable hematological malignancy with high chromosome instability and heavy dependence on the immunosuppressive bone marrow microenvironment. P53 mutations are adverse prognostic factors in MM; however, clinically, some patients without P53 mutations also exhibit aggressive disease progression. DNp73, an inhibitor of TP53 tumor suppressor family members, drives drug resistance and cancer progression in several solid malignancies. Nevertheless, the biological functions of DNp73 and the molecular mechanisms in myelomagenesis remain unclear. The effects of DNp73 on proliferation and drug sensitivity were assessed using flow cytometry and xenograft models. To investigate the mechanisms of drug resistance, RNA-seq and ChIP-seq analyses were performed in MM cell lines, with validation by Western blot and RT-qPCR. Immunofluorescence and transwell assays were used to assess DNA damage and cell invasion in MM cells. Additionally, in vitro phagocytosis assays were conducted to confirm the role of DNp73 in immune evasion. Our study found that activation of NF-κB-p65 in multiple myeloma cells with different p53 mutation statuses upregulates DNp73 expression at the transcriptional level. Forced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells. Bulk RNA-seq analysis was conducted to assess the levels of MYCN, MYC, and CDK7. A ChIP-qPCR assay was used to reveal that DNp73 acts as a transcription factor regulating MYCN gene expression. Bulk RNA-seq analysis demonstrated increased levels of MYCN, MYC, and CDK7 with forced DNp73 expression in MM cells. A ChIP-qPCR assay revealed that DNp73 upregulates MYCN gene expression as a transcription factor. Additionally, DNp73 promoted immune evasion of MM cells by upregulating MYC target genes CD47 and PD-L1. Blockade of the CD47/SIRPα and PD-1/PD-L1 signaling pathways by the SIRPα-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively. In summary, our study demonstrated for the first time that the p53 family member DNp73 remarkably induces proliferation, drug resistance, and immune escape of myeloma cells by directly targeting MYCN and regulating the MYC pathway. The oncogenic function of DNp73 is independent of p53 status in MM cells. These data contribute to a better understanding of the function of TP53 and its family members in tumorigenesis. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients.

Boosting Cancer Immunotherapy via Reversing PD-L1-Mediated Immunosuppression with a Molecularly Imprinted Lysosomal Nanodegrader.

Immune checkpoint blockade therapy has achieved important clinical advances in several types of tumors, particularly via targeting the PD-1/PD-L1 axis. However, existing therapeutic strategies that suppress the PD-1/PD-L1 signal pathway usually experience low treatment efficacy and the risk of causing autoimmune diseases. Herein, we report a cancer cell-targeted molecularly imprinted lysosomal nanodegrader (MILND) for boosting immune checkpoint blockade therapy against tumors. The MILND, imprinted with the N-terminal epitope of PD-L1 as an imprinting template, could specifically target the PD-L1 on tumor cells to promote cellular uptake. This process further induces the transport of PD-L1 into lysosomes for degradation, ultimately resulting in the downregulation of PD-L1 expression levels on tumor cells. As a result, a T cell-mediated immune response in the body was activated via the blockade of the PD-1/PD-L1 signaling pathway, which triggered a durable antitumor efficacy. In vivo experiments demonstrated that the MILND could effectively accumulate in tumor sites and exhibit strong tumor growth suppression efficacy in a xenograft tumor model without obvious side effects. Therefore, the MILND provides not only a promising strategy for boosting cancer immunotherapy but also insights for developing molecular imprinting-empowered nanomedicines.

Abstract Mo015: Myeloid Specific PD-L1 Deletion Promotes Cardiac Dysfunction And Myocardial Inflammation

Background: Immunotherapy, particularly PD-1/PD-L1 blockers, is effective in cancer treatment but can cause rare, but potentially fatal heart issues. Despite the significant impact of these adverse events, there is limited research into the underlying mechanisms of immune checkpoint inhibitor (ICI)-mediated cardiotoxicity. PD-L1, which is abundantly expressed in cardiac tissue, particularly exhibits high expression levels over myeloid cells. However, the precise role of myeloid-specific PD-L1 signaling in mediating autoimmune cardiac disease pathology remains unclear. Methods and Results: To study the role of myeloid cell-specific PD-L1 (myeloid-PD-L1) in cardiac pathophysiology, we generated myeloid-specific PD-L1 KO mice, using Lyz2tm1(Cre) Ifo systems. As expected, PD-L1 expression was significantly down-regulated in Mφs from myeloid-PD-L1 KOs. The cardiac function was followed by echocardiography. Controls and myeloid-PD-L1-KO hearts had comparable ventricular function at 1 month of age. Interestingly, as early as 2 months of age, myeloid-PD-L1-KOs displayed marked cardiac dysfunction as reflected by reduced LVEF, LVFS, and HF markers. Immune profiling was conducted whether chronic inflammation contributes to cardiac dysfunction and remodeling at a later age as observed at 2 and 3 months of age. Interestingly, excessive systemic inflammation and substantial immune infiltration (innate and adoptive), activation, and a pro-inflammatory cytokine storm were detected in the KO hearts. Furthermore, myeloid-PD-L1 KO hearts showed increased recruitment of pro-inflammatory CCR2+ monocytes and macrophages. Conclusion: Our data with myeloid-PD-L1 KOs suggest that deleting PD-L1 in myeloid lineage promotes myocardial and systemic inflammation through innate and adaptive immune cell activation and recruitment of CCR2+ MΦs. Subsequently, this leads to impaired cardiac pathophysiology. Thus, these translational studies will directly evaluate the potential of targeting myeloid-PD-L1 signaling to alleviate cardiac damage.

Evidence of Programmed Death-Ligand 1 Expression in a Highly Inflammatory Prostate: A Literature Review and Our Experience.

Chronic inflammation (CI), a common finding in the human prostate, is associated with the most frequent socially important prostate diseases: prostatitis, benign prostatic hyperplasia, and prostate adenocarcinoma. Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) expression are induced on the surface of immune and epithelial cells of healthy and tumor tissues in response to various cytokines. Here, we provide a comprehensive review of the PD-1/PD-L1 pathway in the non- and peri-tumoral inflammatory prostate, focusing on the structure and expression of PD-L1 and the diverse biological functions of PD-L1 signaling in health, high-grade CI (National Institutes of Health, category IV prostatitis or histologic prostatitis), and immune-related diseases, including autoimmunity, tumor microenvironmental immunity, and immune privilege. This review explores the possible pathophysiological interpretations of clearly visible, selective, and strong PD-L1 expression in the immuno-inflammatory-induced and related, histologically distinct sites of this expression: the ductal lymphoepitheliallesions and prostatic granulomas.

IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance.

IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies.

Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response

Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory Tcells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

Computational Approach for the Development of pH-Selective PD-1/PD-L1 Signaling Pathway Inhibition in Fight with Cancer.

Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment.

Engineered Immunologic Niche Monitors Checkpoint Blockade Response and Probes Mechanisms of Resistance.

Antibodies to programmed cell death protein1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10-20% of PD-L1+ metastatic TNBC patients who meet criteria benefit from ICB, and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance.

The role of immunotherapy in urological cancers.

Immunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. A deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. Historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (ICIs) has been critical to urology. Urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. Intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. These agents increase the anti-tumour response by affecting the body's defence mechanisms. Immunotherapeutic agents used in urothelial carcinoma include various options such as BCG, interferon, anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 (atezolizumab, avelumab, durvalumab). Renal cell carcinoma (RCC) has been known for many years as a tumour with unique sensitivity to immunotherapies. The recent emergence of ICIs that block PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) or CTLA4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced RCC. In light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/ axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic RCC. Prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. Especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. Ipilimumab, nivolumab, pembrolizumab, atezolizumab, and Sipuleucel T (Vaccine-based) are promising alternative treatment options. Considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. In this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials.

The role of PD-1/PD-L1 signaling pathway in cancer pathogenesis and treatment: a systematic review

Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment. Method: This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). All in vitro , in vivo , and clinical studies that were published in English have been considered during a thorough search of the Scopus, Web of Science, and PubMed databases without date restriction until March 2024. Results: According to the studies reviewed, the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer, melanoma, breast cancer, hepatocellular carcinoma, squamous cell carcinoma, and colorectal cancer, among others. Additionally, research suggests that immune checkpoint inhibitors that block PD1/PD-L1, such as pembrolizumab, atezolizumab, nivolumab, durvalumab, cemiplimab, avelumab, etc. , can effectively prevent tumor cells from escaping the immune system. Moreover, there might be a possible interaction between microbiome, obesity, etc. on immune mechanisms and on the immune checkpoint inhibitors (ICIs). Conclusion: Although we have gained considerable knowledge about ICIs, we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients. This is largely due to the complex interactions between different intracellular pathways, which need to be thoroughly studied. To resolve this issue, it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.

PD-1-CD28-enhanced receptor and CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors

The limited expansion ability and functional inactivation of T cells within the solid tumor microenvironment are major problems faced during in the application of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether TILs carrying a PD-1-CD28-enhanced receptor and CD19 CAR could overcome this limitation and mediate tumor regression. First, anti-tumor effects of PD-1-CD28-enhanced receptor or CD19 CAR modified NY-ESO-1-TCR-T cells to mimic the TILs function (hereafter “PD-1-CD28-TCR-T” or “CD19 CAR-TCR-T” cells, respectively) were tested using the NY-ESO-1 over-expressed tumor cell line in vitro and in a tumor-bearing model. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified through transduction with a plasmid encoding the PD-1-CD28-T2A-CD19 CAR) were evaluated in vivo. PD-1-CD28-TCR-T cells showed a formidable anti-tumor ability that was not subject to PD-1/PD-L1 signaling in vivo. CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor abilities both in vitro and in vivo. Three patients with refractory solid tumors received S-TILs infusion. No treatment-related mortality was observed, and none of the patients experienced serious side effects. One patient with melanoma achieved a partial response, and two patients with colon or kidney cancer achieved long-term stable disease following S-TILs therapy. To the best of our knowledge, this is the first study describing the safety and efficacy of the adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer.

The PD-1 /PD-L1 signaling pathway regulates decidual macrophage polarization and may participate in preeclampsia

The pathogenesis of preeclampsia (PE) has not been elucidated, but immune imbalance is known to be one of the main pathogeneses. Dysfunction of decidual macrophages can lead to PE, and the PD-1/PD-L1 signaling pathway is associated with macrophage polarization. However, the relationship between the influence of the PD-1/PD-L1 signaling pathway on macrophage polarization and the onset of PE has not been fully elucidated. In this study, we analyzed the expression of CD68, iNOS, CD206, PD-1 and PD-L1 and the coexpression of CD68+PD-1+ and CD68+PD-L1+ in the decidual tissue of PE patients (n= 18) and healthy pregnant women (n=20). We found that CD68 and iNOS expression was increased in the decidua of PE patients (P < 0.001) and that CD206, PD-1 and PD-L1 expression and CD68+PD-1+ and CD68+PD-L1+ coexpression were decreased (P < 0.001). To assess the influence of the PD-1/PD-L1 signaling pathway on macrophage polarization, we added an anti-PD-1 mAb (pembrolizumab) or an anti-PD-L1 mAb (durvalumab) during THP-1 differentiation into M1 macrophages. Then, we detected the polarization of CD68+CD80+ macrophages and the expression of iNOS. To examine the effect of macrophage polarization on the invasion ability of trophoblast cells, macrophages were cocultured with HTR8/SVneo cells, and the invasion ability of HTR8/SVneo cells was detected via transwell assays. We found that CD68+CD80+ macrophage polarization was enhanced (P<0.05) and that iNOS expression was greater (P<0.01) in the pembrolizumab group. In the durvalumab group, CD68+CD80+ macrophage polarization and iNOS expression were also increased (P<0.05 and P<0.001). Compared with that in the untreated group, the aggressiveness of HTR8/SVneo cells was decreased in both the pembrolizumab group (P < 0.01) and the durvalumab group (P < 0.001). These findings indicate that the PD-1/PD-L1 signaling pathway may play an important role in the pathogenesis of PE by influencing macrophage polarization and reducing the invasion ability of trophoblasts.

Epithelial−mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer

BackgroundWe investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial−mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy.MethodsPD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed.ResultsRNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-β (TGFβ). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFβ production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration.ConclusionsTumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.