Programmed Cell Death Ligand 1 Expression In Tumor Cells Research Articles

PD-L1 Expression in Colorectal Carcinoma Correlates with the Immune Microenvironment.

Colorectal carcinoma (CRC) is a common malignancy, with its diverse clinical, pathological, and molecular features. The immune microenvironment of a tumor comprises of interplay between various cells and molecules, and has a significant role in deciding the tumor behavior and overall prognosis. PD-L1 (programmed cell death ligand-1) has been implicated in the regulation of the tumor immune microenvironment (TIME). There is limited data regarding the correlation of PD-L1 expression with immune cell profile in CRCs, especially in the Indian setting. The study aimed to assess the PD-L1 expression in CRC tumor cells and its association with TIME, mismatch repair (MMR), and various other clinicopathological parameters. This is a hospital-based, cross-sectional observational study. PD-L1 expression was assessed at the protein level by immunohistochemistry and mRNA level by qRT-PCR. Immune cell markers (CD4, CD8, CD20, FOXP3, and CD163) were interpreted using the ImageJ Fiji platform. Of the 104 cases, 21% were PD-L1 positive and were more common in right-sided CRCs. PD-L1 positive cases showed significantly higher concentrations of all T-cell subsets (CD4+ , CD8+ , and FOXP3+), CD20+ B-cells, and CD163+ macrophages were noted. No statistical significance was seen between PD-L1 expression with clinical profile, pathological subtype, grade or stage, mismatch repair status (proficient vs deficient), and survival. The present study showed a relatively lower frequency of PD-L1 in CRC from the Eastern Indian cohort. The immune cell concentration in the present study was calculated using image analysis-based objectivised methods. Significant correlation of PD-L1 expression in tumor cells with the tumor-infiltrating immune cells indicated its crucial role in the pathobiology of CRC especially by regulating the TIME. Considering the therapeutic implication of PD-L1 in various malignancies, it may be one of the crucial therapeutic targets in a proportion of cases.

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1β.

Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC). We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells. The IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ. Our study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity.

Inhibiting COX-2/PGE2 pathway with biodegradable NIR-Ⅱ fluorescent polymeric nanoparticles for enhanced photodynamic immunotherapy

Photodynamic therapy (PDT) capable of eliciting antitumor immune responses by inducing immunogenic cell death (ICD) holds promise for tumor suppression. However, most photosensitizers suffer from limited degradation, insufficient biocompatibility, and inabilities to generate long-wavelength fluorescence for in vivo tracking. Moreover, PDT has the inherent problem of activating the cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE2) pathway and upregulating programmed cell death ligand 1 (PD-L1) expression, resulting in insufficient efficacy of photodynamic immunotherapy. Herein, we designed and synthesized a dihydroxy-containing BODIPY monomer (MonoBodipy), and then formed the biodegradable polymer (PPDT) by polycondensation reaction, which could generate reactive oxygen species (ROS) for photodynamic immunotherapy and emit near-infrared-Ⅱ (NIR-Ⅱ) fluorescence for bioimaging. Subsequently, we further utilized PPDT to encapsulate the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) to form NPPDT@CXB that could inhibit the COX-2/PGE2 pathway. NPPDT@CXB displayed great anticancer potency on osteosarcoma and ovarian cancer in vitro. Further, NPPDT@CXB could accumulate at tumor site after intravenous administration into tumor-bearing mice, generate ROS, induce ICD cascade, and trigger antitumor immune responses under an 808 nm laser irradiation. The ROS further breaks up thioketal linkages in PPDT, resulting in a rapid CXB release to inhibit the COX-2/PGE2 pathway and then downregulate the PD-L1 expression in tumor cells, which in turn leads to an effective suppression of the primary and distant tumors. This work highlighted a well biocompatible and biodegradable photosensitizer that generates ROS, emits long-wavelength fluorescence, inhibits the COX-2/PGE2 pathway, and downregulates PD-L1 expression simultaneously, exhibiting a robust photodynamic immunotherapy efficacy. This study proposed a new strategy to overcome the inherent problems of photodynamic immunotherapy and pointed out the path of future PDT development.

Immunohistochemical expression of PD-L1 and its correlation with microsatellite status in endometrial and ovarian clear cell carcinomas: a cross-sectional study

BackgroundClear cell carcinoma is an uncommon histologic subtype of ovarian and endometrial carcinoma with poor response to Platinium-based chemotherapy agents at high stages. Blockage of Programmed cell Death Ligand-1 (PD-L1), can be used in targeted immunotherapy. This study investigated Mismatch Repair Deficiency (MMR-D) status, PD-L1 expression, and the correlation between PD-L1 expression and microsatellite instability (MSI) status in ovarian and endometrial clear cell carcinomas.MethodsOvarian clear cell carcinoma (OCCC) (n = 28) and endometrial clear cell carcinoma (ECCC) (n = 28) samples were evaluated for PD-L1 (in tumoral and peri-tumoral inflammatory cells), MSH6 and PMS2 expression by immunohistochemistry (IHC) study. PD-L1 expression > 1% in tumor cells and > 5% in peritumoral inflammatory cells were considered positive.ResultsThe prevalence of PD-L1 expression was higher in ECCC (20/28, 71.43%) compared to OCCC tumor cells (16/28, 57.15%) (p > 0.05), while expression in peritumoral inflammatory cells was significantly higher in ECCC (25/28, 89.29%) compared to OCCC (11/28, 39.28%) (p < 0.05). MMR-D was observed in 5 cases, four OCCCs and one ECCC, among which, four (80%) showed PD-L1 expression in peritumoral inflammatory and tumor cells. The only OCCC case with extensive PD-L1 expression in tumor cells (> 50%) exhibited MSH6/MSH2 loss. No significant correlation was noted between PD-L1 expression and the pathologic stage or survival.ConclusionPD-L1 expression was significantly associated with clear cell morphology, especially in the endometrium, independent of MMR protein status.

A retrospective study of PD-L1 immunohistochemistry for hepatocellular carcinoma

Programmed cell death ligand 1 (PD-L1) expression plays an important role in selecting hepatocellular carcinoma (HCC) patients who will benefit from anti-programmed cell death 1 (PD-1)/PD-L1 monotherapy and directing those with lower levels to alternative treatments. In total, 156 HCC tumors were stained with three PD-L1 immunohistochemistry assays (SP142, 28-8, and E1L3N). Two junior pathologists and one senior pathologist evaluated the pathological slides and recorded the percentages of tumor and immune cells stained at any intensity. Analytical comparisons demonstrated that the anti-PD-L1 assay SP142 is a significantly stronger reagent that stains a higher percent of both tumor and immune cells, while 28-8 and E1L3N behave similarly to each other. The correlation coefficients of the three assays ranged from 0.77 to 0.92 for tumor cells and from 0.66 to 0.75 for immune cells. Next, 1% and 5% tumor cell staining cutoffs were designated using various combinations of assays and cutoffs. Across all three reagents, 14 samples showed concordance above the 5% threshold, eight showed concordance within the 1% to 5% interval, and 93 showed concordance below the 1% threshold. The remaining 41 samples showed a combination of discordant results across all three reagents. High PD-L1 expression in tumor and immune cells tended to not be recurrent. The anti-PD-L1 assays 28-8 and E1L3N were closely aligned with regards to staining tumor and immune cells, whereas SP142 showed higher percentages of staining for both cell types. All three assays indicated greater variability in immune cell staining than in tumor cells.

PD-L1 Expression in Colorectal Adenocarcinoma Is Associated With the Tumor Immune Microenvironment and Epithelial-Mesenchymal Transition.

Colorectal carcinomas are the third-most common tumors in the world, and colorectal cancer ranks second in cancer-related deaths. Our aim in this study was to investigate the correlation between programmed cell death ligand 1 (PD-L1) expression and clinicopathologic parameters in colorectal carcinomas and their relationship to the tumor immune microenvironment, epithelial-mesenchymal transition (EMT), and microsatellite instability. We also investigated the predictive and prognostic role of PD-L1. One hundred patients with a diagnosis of colorectal adenocarcinoma who did not receive neoadjuvant therapy were included in the study. The relationships among the altered expression of PD-L1; vimentin; E-cadherin; mismatch repair status; and pathologic microenvironmental features, including the presence of tumor budding and CD8-positive tumor infiltrating lymphocytes (TILs), were assessed. Increased PD-L1 expression in tumor cells was associated with increased TILs (P = .013), high histologic grade (P = .011), advanced pathologic T stage (P = .007), lymph node metastasis (P = .002), distant metastasis (P < .001), perineural invasion (P = .009), high bud score (P = .023), EMT (P < .001), and shorter disease-free survival (P = .029). Overall, PD-L1 expression in colorectal carcinoma tumor cells is a marker of poor prognosis, and the positive correlation detected between EMT status and PD-L1 expression suggests that patients with the mesenchymal phenotype may be more likely to benefit from programmed cell death 1 protein/PD-L1 immunotherapy.

The worsening impact of programmed cell death ligand 1 in ovarian clear cell carcinomas.

To investigate the clinical significance of programmed cell death ligand 1 (PD-L1) expression in ovarian clear cell carcinoma (CCC). Patients with CCC who underwent primary surgery at our hospital between 1984 and 2014 were enrolled in this study. PD-L1 and mismatch repair (MMR) protein expression in tumor cells, tumor-infiltrating lymphocytes (TILs), including cluster of differentiation (CD) 8, CD4, forkhead box P3 (FOXP3), programmed cell death 1 (PD-1), and BAF250a, were evaluated using immunohistochemistry. The association between PD-L1 expression, clinicopathological features, prognosis, and expression of several proteins was investigated. Of the 125 patients with CCC, 17 had negative PD-L1 and 108 had positive PD-L1. Patients with positive PD-L1 expression showed a lower response to chemotherapy (p = 0.01). In addition, patients with positive PD-L1 showed worse progression-free survival (PFS, p = 0.01) and overall survival (OS, p = 0.01) than that in patients with negative PD-L1 expression. Multivariate analyses for PFS and OS showed that PD-L1 expression was an independent prognostic factor for PFS (hazard ratio [HR] 7.81, p < 0.01) and OS (HR 12.90, p < 0.01). PD-L1 expression was not associated with the expression of several TILs or proteins. The expression of PD-L1 was related to a lower response to chemotherapy and worse prognosis in CCC. These results may be useful for the development of new treatments.

Immunotherapy in Penile Squamous Cell Carcinoma: Present or Future? Multi-Target Analysis of Programmed Cell Death Ligand 1 Expression and Microsatellite Instability.

BackgroundPenile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs.MethodsA series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status.ResultsOf the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status.ConclusionOur findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.

PD-L1 expression in invasive solid papillary breast carcinomas.

Invasive solid papillary carcinomas (ISPC) are rare malignant neoplasms in the classification of WHO 2019 breast tumors. We aimed to investigate the correlations between programmed cell death ligand-1 (PD-L1) expression status of tumor and immune cells and clinicopathological parameters by molecular classification of this rare morphological subtype. This study will contribute to the literature about the PD-L1 expression state of ISPCs for the first time. The study included 19 invasive solid papillary carcinoma cases diagnosed between 2009 and 2019 in Pathology Department. Molecular subtyping was performed in 19 cases by immunohistochemical studies (ER/PR, Her-2/neu, Ki-67), and PD-L1 expression was evaluated in neoplastic and immune cells. PD-L1 expression was detected in 4 (21%) cases, 3 (75%) of them were in luminal B and 1 (25%) were in the luminal A group. The correlation between molecular subtypes and PD-L1 expression was statistically significant (P = 0.016). Patients with PD-L1 expression had a higher Ki-67 index than patients without PD-L1 expression (P = 0.037). In addition, there was a statistically significant correlation between PD-L1 expressions of intratumoral lymphocytes and PD-L1 expressions of neoplastic cells (P = 0.004). While predicting the group that will benefit more from immunotherapy in solid papillary carcinoma cases, not only PD-L1 expression of tumor cells but also PD-L1 expression in tumor infiltrating lymphocyte (TIL) can help. In addition, PD-L1 staining rates of tumor cells as well as clinicopathological parameters (molecular subtype, high Ki-67 index, presence of TIL) can be predictive about immunotherapy.

Engineered EGCG‐Containing Biomimetic Nanoassemblies as Effective Delivery Platform for Enhanced Cancer Therapy

Nano‐based immunotherapy of therapeutic biomolecules is attractive but tremendously hampered by the poor delivery efficiency. This study reports a novel delivery system of fluorinated‐coordinative‐epigallocatechin gallate (EGCG), referring as FEGCG/Zn, through the integration of fluorination and zinc ions (Zn2+) into EGCG. The robust therapeutics of FEGCG/Zn are measured in terms of the regulating effect on programmed cell death ligand 1 (PD‐L1), the effective delivery of diverse biomolecules, and the hitchhiking ability using living cells. Taking small interfering RNA of PD‐L1 (siPD‐L1) and erythrocytes as an example, the fabricated biomimetic system achieves excellent siPD‐L1 delivery and further improves siPD‐L1 accumulation in tumors. Finally, the combination of FEGCG/Zn and siPD‐L1 promotes antitumor immunotherapy through alleviation of T cells exhaustion by regulating PD‐L1 expression in tumor cells. The results demonstrate that FEGCG/Zn substantially regulates PD‐L1 expression and improves immune‐biomolecule delivery by forming biomimetic nanoassemblies, offering a versatile platform for cancer immunotherapy.

The effects of immune checkpoint modulators on the clinical course of patients with resectable hepatocellular carcinoma.

Immune checkpoint proteins regulating T-cell mediated anti-tumor immunity have been reported to affect clinical outcomes in multiple malignancies. This study aimed to investigate the prognostic effect of histological expression of immune checkpoint proteins in patients with resected hepatocellular carcinoma (HCC). A total of 221 patients with HCC who underwent curative resection were included. Expression of programmed-cell death ligand-1 (PD-L1) in tumor cells (tPD-L1) and tumor infiltrating mononuclear cells (TIMCs) (iPD-L1), programmed-cell death-1 in TIMCs (iPD-1), and cytotoxic T lymphocyte antigen-4 in TIMCs (iCTLA-4) were measured immunohistochemically. Histo-positivity for iCTLA-4, iPD-1, iPD-L1, and tPD-L1 was 32.1%, 42.5%, 35.3%, and 14.9%, respectively. Multivariate logistic analyses revealed that male sex and tumor >5 cm were variables related to iCTLA-4 positivity (odds ratio [OR], 0.46 and 1.94, respectively; P<0.05). Poor differentiation was related to PD-L1 expression in both tumor cells and TIMCs (OR, 2.88 and 3.46, respectively; P<0.05). Microvascular invasion was significantly associated only with iPD-L1 (OR, 2.24; P<0.05). In time-dependent outcome analyses, expression of immune checkpoint proteins in TIMCs (i.e., iCTLA-4, iPD-1, and iPD-L1) was significantly related to longer overall survival and non-cancer-related survival (all P<0.05), but not to time-to-recurrence or cancer-specific deaths. Concurrent activation of the PD-1:PD-L1 and CTLA-4 pathways predicted improved outcomes in terms of overall survival and non-cancer related survival (P=0.06 and P=0.03, respectively). Immune checkpoint proteins upregulated in TIMCs in HCC tissues have individual and additive effects in prolonging the survival of patients, specifically in terms of survival not related to cancer recurrence.

Clinicopathological correlation and prognostic value of PD-L1 expression in renal cell carcinoma

Introduction: The expression of programmed cell death-ligand 1 (PD-L1) and its correlation with the prognosis of renal cell carcinoma (RCC) remains controversial. Objectives: This study aimed to study PD-L1 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in patients with RCC and its association with clinicopathological factors and survival outcomes. Patients and Methods: PD-L1 expression in tumor cells and TILs was analyzed using immunohistochemistry (IHC) from patients with histologically proven RCC. Results: PD-L1 was positive in tumor cells for 55.8% of patients. PDL-1 expression in TIL was reported in 31.2 % of patients. Patients with PDL1 positive tumor cells had higher median tumor size (P=0.07), higher nuclear grade (P=0.56), and higher lymphovascular invasion (LVI) (P=0.23). Patients with PDL1 positive TILs were significantly associated with larger median pathological tumor size (P=0.02), higher probability of renal fat invasion (P=0.001), higher nuclear grade (P=0.05), higher probability of positive margin (P=0.02), positive LVI (P=0.03), higher pathological T stage (P=0.0004); whereas patients with PDL-1 negative TILs had earlier stage at presentation (stage I-II) (P=0.004). There was no statistically significant difference in disease-free survival (DFS), progression-free survival (PFS), or overall survival (OS) for PD-L1 expression of tumor cells and TILs. Conclusion: PDL1 positivity in TILs and not in tumor cells was significantly associated with more aggressive features, and higher stage. No association was found with DFS, PFS, or OS. These data suggest that PD-L1 expression of TILs in RCC tumors contributes to cancer aggressiveness.

Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma

In many types of cancer, tumor cells prefer to use glycolysis as a major energy acquisition method. Here, we found that the 18fluoro-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based markers were positively associated with the expression of programmed cell death ligand 1 (PD-L1), pyruvate kinase M2 (PKM2), both of which indicate poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. In this study, we confirmed that transforming growth factor-beta1 (TGF-β1) secreted by tumor-associated macrophages (TAMs) was a key factor contributing to the expression of PD-L1 in PDAC cells by inducing the nuclear translocation of PKM2. Using co-immunoprecipitation and chromatin immunoprecipitation assays, we demonstrated that the interaction between PKM2 and signal transducer and activator of transcription 1 (STAT1) was enhanced by TGF-β1 stimulation, which facilitated the transactivation of PD-L1 by the binding of PKM2 and STAT1 to its promoter. In vivo, PKM2 knockdown decreased PD-L1 expression in PDAC cells and inhibited tumor growth partly by promoting natural killer cell activation and function, and the combination of PD-1/PD-L1 blockade with PKM2 knockdown limited tumor growth. In conclusion, PKM2 significantly contributes to TAM-induced PD-L1 overexpression and immunosuppression, providing a novel target for immunotherapies for PDAC.

Strong expression of PD-L1 in invasive front of MELF pattern in endometrioid carcinoma

Endometrioid carcinoma (EC) is classified into 3 histological subtypes; Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3). Although the prognosis is relatively good in G1, some G1 cases are more aggressive, which are called G1 with MELF (microcystic, elongated, and fragmented) pattern. Current therapy, such as radiotherapy and chemotherapy, is not effective in MELF, and more effective treatment is needed. The Cancer Genome Atlas (TCGA) performed an integrated genomic, transcriptomic, and proteomic analysis and classified EC into 4 groups: DNA polymerase epsilon (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high, in which MELF was associated with microsatellite instability hypermutated. Microsatellite instability is detected in a wide variety of cancer, and PD-1 (programmed cell death 1) and PD-L1 (programmed cell death-ligand 1) are received a lot of attention as a therapeutic target. To date, no studies have been focused on PD-L1 expression in EC with MELF pattern. Then we performed immunohistochemical analysis of the distribution of PD-L1 expressing cells in G1 with MELF pattern. In cases of G1 with MELF pattern, tumor cells expressed PD-L1 significantly higher in invasive front area than in surface area. We often found lymphovascular invasion of PD-L1 expressing tumor cells. PD-L1 expressing tumor cells in MELF would be the cause of recurrence or lymph node metastasis. Moreover, in most G1 cases with MELF pattern, PD-L1 was expressed in inflammatory cells as well as tumor cells in invasive front area. PD-L1 expression in both tumor and immune cells contribute to immune suppression and both cells could be sensitive to therapeutic agents targeting the PD-L1/PD-1 axis. Therefore, significant therapeutic effect can be expected by applying PD-1/PD-L1 immunotherapy to the treatment of G1 with MELF.

Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer.

Simple SummaryPD-L1 is an important immune checkpoint molecule that is expressed in cancer tissues at various levels and plays a major role in tumor evasion from immune system. Therefore, understanding the mechanisms by which PD-L1 expression is regulated in tumor environment is important for the design of new therapeutic strategies to overcome tumor immune escape and improve the outcome of cancer treatment. Recent studies suggest that genetic, epigenetic, and transcriptional factors as well as posttranscriptional and posttranslational processes are crucial regulators of PD-L1 expression in tumor cells. This review focuses on two newly described regulations of PD-L1 mediated by oncogenes, and redox homeostasis. In this context, a recent research work describes the important role of oncogenic K-ras, growth factor receptors (FGFR1 and EGFR) and ROS in regulating PD-L1 expression in pancreatic cancer cells and aids significant new mechanistic insights in this important area.Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.

PD-L1 expression in tumor cells is associated with a favorable prognosis in patients with high-risk endometrial cancer

ObjectiveTo investigate programmed cell death ligand 1 (PD-L1) expression patterns and define the associations among PD-L1, molecular subtypes, pathological features, and survival in a cohort of 833 patients with endometrial cancer, of whom approximately half had high-risk disease. MethodsUsing direct sequencing of the polymerase epsilon (POLE) exonuclease domain as well as immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6) and p53, we stratified endometrial cancers into four molecular subtypes: POLE ultramutated, MMR-deficient, p53-mutant, and non-specific molecular profile (NSMP). PD-L1 was detected via immunohistochemistry and evaluated in tumor cells (TCs) and immune cells (ICs) individually and using the combined positive score (CPS). ResultsPositive PD-L1 staining in TCs (≥1%), ICs (≥1%), and in combination (CPS ≥1) was detected in 14.0%, 37.3%, and 45.1% of the samples, respectively. PD-L1 positivity in TCs was more frequent in high-grade than in low-grade tumors, while that in ICs was associated with lymphovascular space invasion, non-endometrioid histology, and deep myometrial invasion. PD-L1 expression in both TCs and ICs was more frequent in POLE ultramutated and MMR-deficient subtypes than in p53-mutant and NSMP subtypes. PD-L1 positivity in TCs, but not in ICs or combined (CPS), was associated with a favorable prognosis in patients with high-risk endometrial cancer. ConclusionsThe distribution and prognostic significance of PD-L1 in TCs versus ICs differ in patients with endometrial cancer, indicating that the separate assessment of PD-L1 in these cells (rather than determining the CPS) may be more relevant to selecting patients eligible for endometrial cancer immunotherapy.

MiR-194-5p down-regulates tumor cell PD-L1 expression and promotes anti-tumor immunity in pancreatic cancer

Pancreatic cancer is a highly malignant cancer of the digestive tract. Studies have shown that in some types of cancer, a high level of microRNA-194-5p (miR-194-5p) is beneficial for controlling tumor progression, while in other cancers it plays a completely opposite role. However, how miR-194-5p affects anti-tumor immunity of pancreatic cancer remains unclear. In this study, we found that high expression of miR-194-5p in human pancreatic cancer patients is associated with a better survival rate, while increased expression of programmed cell death ligand 1 (PD-L1) in human pancreatic cancer patients is associated with a worse survival rate. In pancreatic cancer, the expression level of PD-L1 is negatively correlated with the expression level of miR-194-5p, and we identified that PD-L1 was target gene of miR-194-5p. In addition, we found that overexpression of miR-194-5p inhibited the migration, invasion and proliferation of pancreatic cancer cells in vitro. The orthotopic mouse model of pancreatic cancer shown that miR-194-5p suppressed the progression of pancreatic cancer, promoted the infiltration of CD8+ T cells in tumor immune microenvironments, and enhanced the IFN-γ production of CD8+ T cells. Consistently, the co-culture experiments showed that overexpression of miR-194-5p in tumor cell enhanced IFN-γ production by CD8+ T cells. In conclusion, miR-194-5p may serve as a novel immunotherapeutic target for pancreatic ductal adenocarcinoma (PDAC) by inhibiting the expression of PD-L1, and play important roles in inhibiting the progression of pancreatic cancer and boosting the anti-tumor effect of CD8+ T cells.

PD-L1 expression and patient outcomes in gastrointestinal neuroendocrine neoplasm: a meta-analysis.

BackgroundProgrammed cell death ligand 1 (PD-L1) is a known prognostic and therapeutic marker in malignant tumors. This meta-analysis aimed to investigate the association of PD-L1 expression with the clinicopathological parameters and survival outcomes of gastrointestinal neuroendocrine neoplasms (NENs).MethodsPubMed, EMBASE, Web of Science, OVID Medline, the Cochrane Library, and Google Scholar were searched for relevant studies June 30, 2020. Studies reporting PD-L1 immunohistochemistry of gastrointestinal NEN with associated survival data or clinicopathological parameters were included.ResultsIn total, 10 studies were included. Odd ratios (ORs) were combined to evaluate association between PD-L1 expression and clinicopathological parameters. Hazard ratios (HR) and standard errors were combined to evaluate the association between PD-L1 expression and overall survival. PD-L1 expression was significantly associated with higher tumor grade [OR: 3.42; 95% confidence interval (CI): 2.00–5.85, P<0.05] and lymph node metastasis (OR: 1.94; 95% CI: 1.13–3.34, P=0.02). However, PD-L1 expression was not associated with age, sex, and tumor stage. The pooled hazard ratio (HR: 2.45, 95% CI: 1.20–4.98, P<0.05) showed a significant association between PD-L1 expression and shorter overall survival.DiscussionThe results of this meta-analysis show that PD-L1 expression in tumor cells of gastrointestinal NEN can be used as a biomarker of worse survival and important clinicopathological parameters. Further, it can also be used as a therapeutic biomarker for developing novel treatment modalities that can improve prognosis. Although the results of this meta-analysis are more robust than those of the individual studies analyzed, this study also has several limitations. Further studies with a larger study population and consistent method for evaluating PD-L1 expression are needed to validate our results.

Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy

Programmed cell death-ligand 1 (PD-L1)-based immune checkpoint blockade therapy using the anti-PD-L1 antibody is effective for a subset of patients with advanced metastatic melanoma but about half of the patients do not respond to the therapy because of the tumor immunosuppressive microenvironment. Immunogenic cell death (ICD) induced by cytotoxins such as doxorubicin (DOX) allows damaged dying tumor cells to release immunostimulatory danger signals to activate dendritic cells (DCs) and T-cells; however, DOX also makes tumor cells upregulate PD-L1 expression and thus deactivate T-cells via the PD-1/PD-L1 pathway. Herein, we show that celastrol (CEL) induced not only strong ICD but also downregulation of PD-L1 expression of tumor cells. Thus, CEL was able to simultaneously activate DCs and T-cells and interrupt the PD-1/PD-L1 pathway between T-cells and tumor cells. In a bilateral tumor model, intratumorally (i.t.) injected celastrol nanoemulsion retaining a high tumor CEL concentration activated the immune system efficiently, which inhibited both the treated tumor and the distant untreated tumor in the mice (i.e., abscopal effect). Thus, this work demonstrates a new and much cost-effective immunotherapy strategy — chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.