Programmed Death Ligand Research Articles

Chimeric Peptide-Engineered Polyprodrug Enhances Cytotoxic T Cell Response by Inducing Immunogenic Cell Death and Upregulating Major Histocompatibility Complex Class I.

Tumor-specific cytotoxic T cell immunity is critically dependent on effective antigen presentation and sustained signal transduction. However, this immune response is frequently compromised by the inherently low immunogenicity of breast cancer and the deficiency in major histocompatibility complex class I (MHC-I) expression. Herein, a chimeric peptide-engineered stoichiometric polyprodrug (PDPP) is fabricated to potentiate the cytotoxic T cell response, characterized by a high drug loading capacity and precise stoichiometric drug ratio, of which the immunogenic cell death (ICD) inducer of protoporphyrin IX (PpIX) and the epigenetic drug of decitabine (DAC) are condensed into a polyprodrug called PpIX-DAC. Furthermore, programmed death ligand 1 (PD-L1) targeting peptide sequence (CVRARTR) is conjugated onto DSPE-PEG2000-Mal for encapsulation of PpIX-DAC, thereby enhancing breast cancer-targeted drug delivery. PDPP exerts its antitumor effects through photodynamic therapy (PDT), ablating breast cancer cells while concurrently inducing the release of damage-associated molecular patterns (DAMPs) to boost tumor immunogenicity. Additionally, PDPP can upregulate MHC-I expression via epigenetic modulation, synergistically augmenting the cytotoxic T cell response together with a PD-L1 blockade. In short, PDPP induces a robust antitumor T cell immunity, causing effective eradication of primary and metastatic breast cancer. This study may inspire the development of stoichiometric nanomedicine for clinical translation.

Sex-specific Molecular Markers NRF2 and PD-L1 in Colon Carcinogenesis: Implications for Right-sided Colon Cancer.

This study examined the roles of nuclear factor erythroid 2-related factor 2 (NRF2) and programmed death ligand 1 (PD-L1) in colon carcinogenesis, underscoring on sex and differences in tumor location. A total of 378 participants were enrolled from Seoul National University Bundang Hospital: 88 healthy controls (HC), 139 patients with colorectal adenoma (AD), and 151 patients with colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (PCR), methylation-specific PCR, and immunohistochemistry (IHC) were performed utilizing tumor samples from patients and normal mucosa in the HC group. NRF2 mRNA expression was higher in the CRC group than in the HC and AD groups, with decreased NRF2 methylation in the AD and CRC groups. NRF2 protein expression, as evaluated by IHC, increased in the AD and CRC groups relative to that in the HC group. PD-L1 protein expression was remarkably higher in the CRC group than in the HC and AD groups. These patterns were consistent in both males and females. In sex- and CRC location-specific analyses, NRF2 methylation was lower in female than in male patients with CRC. NRF2 protein expression was significantly higher in females, particularly in patients with right-sided CRC. Moreover, females exhibited increased PD-L1 mRNA expression compared to males in the AD group, and PD-L1 mRNA levels were higher in females with right-sided CRC than in those with cancer at other locations. Differences in NRF2 and PD-L1 expression indicate site-specific colon carcinogenesis based on sex, particularly in females with right-sided CRC.

Comparison of Antitumor Effects of Combinations of Immune Checkpoint Inhibitors With Dendritic Cells Intratumorally Injected into Irradiated Mouse Adenocarcinoma.

Dendritic cells (DCs) are specialized immune cells that play a crucial role in presenting antigens and activating cytotoxic T lymphocytes to combat tumors. The immune checkpoint receptor programmed cell death-1 (PD-1) can bind to its ligand programmed cell death-ligand 1 (PD-L1), which is expressed on the surface of cancer cells. This interaction suppresses T-cell activation and promotes immune tolerance. Radiation therapy can increase the expression of PD-L1 on tumor cells, which can lead to a decrease in the effectiveness of the treatment, and detailed studies are needed to understand the mechanisms. As many patients develop resistance to chemotherapy and radiotherapy-either through lack of response or cancer recurrence-there is a critical need to maximize synergistic effects by selecting combination treatments that offer improved therapeutic efficacy with minimal side effects. In the present study, immature DCs (iDCs) were introduced directly into irradiated tumor sites (referred as IR/iDCs), and immune checkpoint blockades (ICBs) were administered intraperitoneally. We confirmed the antitumor effect of combining IR/iDCs and ICBs by examining tumor growth and mouse survival. The proportion of CD4+ and CD8+ T cells in splenocytes increased in the IR/iDCs-treated groups. Combining IR/iDCs with an anti-PD-L1 antibody led to a significant reduction in distant tumor growth and improved mouse survival rates compared with IR/iDCs alone or IR/iDCs + anti-PD-1 antibody. These findings suggest that integrating radiotherapy, DC-based immunotherapy, and ICB, specifically targeting PD-L1, may be an effective cancer treatment strategy.

Emerging strategies in cancer immunotherapy: Expanding horizons and future perspectives

Cancer immunotherapy has revolutionized oncology by harnessing the body’s immune system to target and eradicate malignant cells. This review delves into emerging strategies in cancer immunotherapy, focusing on novel approaches and future directions of this rapidly evolving field. Key areas of exploration include immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines. ICIs, which target proteins such as cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/programmed cell death ligand 1, have shown significant efficacy in various cancers, transforming clinical outcomes. CAR-T cell therapy, with its ability to genetically modify T-cells to attack cancer cells, has demonstrated remarkable success in hematologic malignancies and is being adapted for solid tumors. Cancer vaccines designed to stimulate an immune response against specific tumor antigens are also advancing with promising clinical results. Despite these advances, challenges such as immunogenicity, side effects, and treatment resistance remain. This review provides a comprehensive overview of the latest developments, clinical trials, and future perspectives in cancer immunotherapy, highlighting the potential for these strategies to redefine cancer treatment.

Effect of immune checkpoint inhibitors on patients with hepatitis B virus infection.

Hepatitis B virus (HBV) infection is regarded as a major health concern worldwide. In patients with chronic HBV infection, exhausted virus-specific CD8+ T cells, resulting from the activation of the programmed cell death protein 1 and programmed death ligand 1 axis, play a key role in the chronicity of infection. Functional cure for HBV, defined as the seroclearance of hepatitis B surface antigen (HBsAg), is viewed as the optimal goal of chronic HBV infection treatment because HBsAg loss is associated with a low risk of hepatocellular carcinoma and a relatively favorable prognosis. Both interferon treatment and finite antiviral therapy have been found to be associated with positive HBV outcomes. Overall, combining immune checkpoint inhibitors with nucleos(t)ide analogs appears to be a promising approach for achieving HBsAg loss, particularly in patients with low HBsAg levels.

Deep Learning Model for Predicting Immunotherapy Response in Advanced Non−Small Cell Lung Cancer

Only a small fraction of patients with advanced non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitor (ICI) treatment. For optimal personalized NSCLC care, it is imperative to identify patients who are most likely to benefit from immunotherapy. To develop a supervised deep learning-based ICI response prediction method; evaluate its performance alongside other known predictive biomarkers; and assess its association with clinical outcomes in patients with advanced NSCLC. This multicenter cohort study developed and independently validated a deep learning-based response stratification model for predicting ICI treatment outcome in patients with advanced NSCLC from whole slide hematoxylin and eosin-stained images. Images for model development and validation were obtained from 1 participating center in the US and 3 in the European Union (EU) from August 2014 to December 2022. Data analyses were performed from September 2022 to May 2024. Monotherapy with ICIs. Model performance measured by clinical end points and objective response rate (ORR) differentiation power vs other predictive biomarkers, ie, programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs). A total of 295 581 image tiles from 958 patients (mean [SD] age, 66.0 [10.6] years; 456 [48%] females and 502 [52%] males) treated with ICI for NSCLC were included in the analysis. The US-based development cohort consisted of 614 patients with median (IQR) follow-up time of 54.5 (38.2-68.1) months, and the EU-based validation cohort, 344 patients with 43.3 (27.4-53.9) months of follow-up. The ORR to ICI was 26% in the developmental cohort and 28% in the validation cohort. The deep learning model's area under the receiver operating characteristic curve (AUC) for ORR was 0.75 (95% CI, 0.64-0.85) in the internal test set and 0.66 (95% CI, 0.60-0.72) in the validation cohort. In a multivariable analysis, the deep learning model's score was an independent predictor of ICI response in the validation cohort for both progression-free (hazard ratio, 0.56; 95% CI, 0.42-0.76; P < .001) and overall survival (hazard ratio, 0.53; 95% CI, 0.39-0.73; P < .001). The tuned deep learning model achieved a higher AUC than TMB, TILs, and PD-L1 in the internal set; in the validation cohort, it was superior to TILs and comparable with PD-L1 (AUC, 0.67; 95% CI, 0.60-0.74), with a 10-percentage point improvement in specificity. In the validation cohort, combining the deep learning model with PD-L1 scores achieved an AUC of 0.70 (95% CI, 0.63-0.76), outperforming either marker alone, with a response rate of 51% compared to 41% for PD-L1 (≥50%) alone. The findings of this cohort study demonstrate a strong and independent deep learning-based feature associated with ICI response in patients with NSCLC across various cohorts. Clinical use of this deep learning model could refine treatment precision and better identify patients who are likely to benefit from ICI for treatment of advanced NSCLC.

The Role of YY1 in the Regulation of LAG-3 Expression in CD8 T Cells and Immune Evasion in Cancer: Therapeutic Implications

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.

A prospective phase Ⅱ clinical trial of toripalimab combined with platinum-based concurrent chemoradiotherapy and consolidation chemotherapy in patients with locally advanced cervical cancer

Objective: To explore the efficacy and safety of toripalimab combined with platinum-based chemoradiotherapy in the treatment of locally advanced cervical cancer. Methods: A total of 82 patients diagnosed as locally advanced cervical cancer who received toripalimab combined with platinum-based concurrent chemoradiotherapy at Tianjin Medical University Cancer Institute and Hospital from May 24th 2019 to August 31st 2022 were enrolled prospectively. After undergoing concurrent chemoradiotherapy, the patient received six cycles of treatment with toripalimab in combination with paclitaxel and platinum-based agents. The primary endpoint of the study was the objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), safety, progression-free survival, and overall survival. Kaplan-Meier curves were used to depict the cumulative incidence of progression-free survival (PFS) and overall survival (OS) for patients with different expression levels of programmed death-ligand 1 (PD-L1) and genetic mutation burdens, and log-rank tests were used to compare the difference between groups. Results: The median age of the patients was 53.6 (45.5,58.7) years, and 76 patients (92.7%) had squamous cell carcinoma. The overall ORR and DCR for the 82 patients were both 87.8% (72 patients, 95%CI: 78.7%-94.0%). Among the 82 patients, 64 (78.0%) achieved complete remission, 8 (9.8%) had partial remission, 8 (9.8%) had disease progression, and 2 (2.4%) were not evaluable. During the treatment, 37 patients (45.1%) experienced treatment-related adverse events, of which 17 patients (20.7%) had grade 3 or higher adverse reactions. The most common grade 3 or higher treatment-related adverse reaction was radiation enteritis (n=5, 6.1%). The median follow-up time was 20.6 (14.0, 27.9) months. The median progression-free survival (mPFS) and median overall survival (mOS) were not reached. The 2-year PFS rate was higher in patients with PD-L1 combined positive score (CPS)≥10 compared to those with CPS<10 (92.4% vs 81.2%, χ²=0.68, P=0.409), and higher in patients with low tumor mutation burden (TMB-L) compared to those with high tumor mutation burden (TMB-H) (95.2% vs 83.3%, χ²=1.91, P=0.167). Conclusion: Patients with locally advanced cervical cancer can achieve favorable objective response rates when treated with toripalimab in combination with platinum-based concurrent chemoradiotherapy and consolidative chemotherapy.

Curzerenone inactivates the nuclear factor-kappa B signaling to suppress malignancy and immune evasion in cervical cancer by targeting CSNK2B.

Curzerenone is a major component of the traditional herbal medicine Curcumae Rhizoma with potential cancer-suppressing effects. This study aims to investigate the treatment effect of Curzerenone on cervical cancer cells and the underpinning mechanism. HeLa and SiHa cells were treated with Curzerenone. The 100μM Curzerenone treatment repressed proliferation, migration, and invasion of the cells. The Curzerenone treatment also reduced cellular expression of programmed death ligand 1, which increased the proliferation and activity of CD8+ T cells in a co-culture system with cancer cells. Casein kinase 2 beta (CSNK2B), a predicted physiological target of Curzerenone, was found to be suppressed by Curzerenone. Further overexpression of CSNK2B blocked the treatment effects of Curzerenone. Curzerenone inhibited while CSNK2B triggered activation of the nuclear factor-kappa B (NF-κB) pathway. The oncogenic and immunosuppressive effects of CSNK2B were blocked by an NF-κB-specific inhibitor. In vivo, Curzerenone treatment inhibited the tumorigenic activity of cancer cells, and it increased the proportion of CD8+ T cells in the xenograft tumor tissues. However, these anti-tumor effects were diminished by the CSNK2B overexpression as well. In conclusion, this research suggests that Curzerenone targets CSNK2B and inactivates the NF-κB signaling to suppress malignancy and immune evasion in cervical cancer.

Caryophylli Cortex Suppress PD-L1 Expression in Cancer Cells and Potentiates Anti-Tumor Immunity in a Humanized PD-1/PD-L1 Knock-In MC-38 Colon Cancer Mouse Model.

Immune checkpoints are essential for regulating excessive autoimmune responses and maintaining immune homeostasis. However, in the tumor microenvironment, these checkpoints can lead to cytotoxic T cell exhaustion, allowing cancer cells to evade immune surveillance and promote tumor progression. The expression of programmed death-ligand 1 (PD-L1) in cancer cells is associated with poor prognoses, reduced survival rates, and lower responses to therapies. Consequently, downregulating PD-L1 expression has become a key strategy in developing immune checkpoint inhibitors (ICIs). Caryophylli cortex (CC), derived from the bark of the clove tree Syzygium aromaticum, possesses antioxidant and cytotoxic properties against cancer cells, yet its potential as an ICI remains unclear. In this study, we aimed to investigate whether CC extract modulates PD-L1 expression in cancer cells and activates T cell immunity through a co-culture system of cancer cells and T cells, as well as in hPD-L1/MC-38 tumor-bearing animal models. Our findings indicate that CC extract significantly downregulated both constitutive and inducible PD-L1 expression at non-toxic concentrations for cancer cells while simultaneously enhancing cancer cell mortality and T cell activity in the co-culture system. Furthermore, the administration of CC extract to hPD-L1/MC-38 tumor-bearing mice resulted in a greater than 70% reduction in tumor growth and increased infiltration of CD8+ T cells within the tumor microenvironment. Principal component analysis identified bergenin, chlorogenic acid, and ellagic acid as active ICIs. These findings suggest that CC extract exerts a potent antitumor effect as an immune checkpoint blocker by inhibiting PD-L1 expression in cancer cells and disrupting the PD-1/PD-L1 interaction.

Beyond first-line therapy: efficacy and safety outcomes of continuing immunotherapy in extensive stage small cell lung cancer after PD-L1 inhibitor progression.

To evaluate the efficacy and safety of the continuing immunotherapy as subsequent therapy in extensive-stage small cell lung cancer (ES-SCLC) patients who have progressed after initial immunotherapy. A retrospective analysis was conducted on patients with ES-SCLC who experienced disease progression after receiving programmed cell death ligand 1 (PD-L1) inhibitors combined with standard chemotherapy as first-line treatment at three sites in China. Patients were divided into two groups according to whether to continue second-line immunotherapy. In a cohort of 150 ES-SCLC patients evaluated post-progression following first-line PD-L1 inhibitors, second-line treatment regimens varied: 86 patients received immunotherapy beyond progression (IBP) and 64 did not proceed to second-line immunotherapy (non-IBP). IBP significantly increased both disease control rates (DCR, 68.6% vs. 32.8%, p<0.001) and overall response rate (ORR, 33.7% vs. 15.6%, p=0.012) and extended median progression-free survival (PFS, 4.1 vs. 2.4 months, HR=0.46, p<0.001) when compared with non-IBP group. The median overall survival (OS) in the IBP group was also longer than that in the non-IBP group (11.2 months vs. 9.0 months, HR=0.68, 95%CI 0.47-0.98, p=0.042). Subgroup analyses revealed a significant survival advantage with IBP treatment in patients presenting with baseline liver metastases, less than three metastatic organs, and those who were nonsmokers. In patients with ES-SCLC who received first-line PD-L1 inhibitors, continuing IBP extended second-line survival without increasing adverse events (AEs). A more pronounced OS benefit with IBP was noted within specific patient subgroups.

Expression and clinical significance of programmed death ligand-1 evaluated by 22C3 antibody in pleural effusion metastatic non-small-cell lung cancer

Objective: Programmed death ligand-1 (PD-L1) is involved in tumor immune escape and is an important target molecule for the immunotherapy of non-small-cell lung cancer (NSCLC). The expression of PD-L1 affects NSCLC invasion, metastasis, and patient survival. This study aims to explore the levels of PD-L1, as identified by the 22C3 antibody, in the malignant pleural effusion of patients suffering from advanced NSCLC, and to determine its clinical implications. Material and Methods: A two-step immunohistochemical EnVision assay was used to evaluate the expression of PD-L1 by the 22C3 antibody in 149 malignant pleural fluid cell wax clots of NSCLC. The relationship between PDL1 expression and clinicopathological characteristics, anaplastic lymphoma kinase (ALK) expression, epidermal growth factor receptor (EGFR) mutation, and overall survival (OS) time of patients with NSCLC was analyzed. Results: Positive expression of PD-L1 in malignant pleural fluid of NSCLC was observed as follows: Positive (&lt;1%: 11.4%), positive (1–49%: 19.5%), and positive (≥50%: 11.4%), with a total positive rate of 42.3%. There was a significant association between PD-L1-positive expression and factors such as tumor differentiation, lymph node metastasis, and metastasis to other organs (P &lt; 0.05). Furthermore, PD-L1 expression showed a positive correlation with ALK expression (rs = 11.49, P &lt; 0.05) but did not correlate with EGFR mutations (rs = 0.004, P &gt; 0.05). Significant differences in median OS were observed between patients exhibiting positive PD-L1 expression and those without, according to survival follow-up data (P &lt; 0.05). Conclusion: Immunohistochemical detection of PD-L1 expression in malignant pleural fluid of advanced NSCLC provides a basis for clinical tumor immunotherapy. Immunohistochemical detection of PD-L1 expression in malignant pleural fluid of advanced NSCLC is minimally invasive, simple, and fast, particularly for metastatic NSCLC where malignant pleural fluid is the first symptom, offering significant clinical application value.

Loss of RPN1 Promotes Antitumor Immunity via PD-L1 Checkpoint Blockade in Triple-negative Breast Cancer--Experimental Studies.

RPN1, also known as ribophorin I (RPN1), is a type I transmembrane protein that plays an important role in glycosylation. However, the effects of RPN1 on cancer progression and immune evasion in breast cancer (BC) have not been identified. The expression of RPN1 was evaluated using RT-qPCR and immunohistochemistry (IHC). The effects of RPN1 on tumor cells were assessed using RT-qPCR, western blotting, flow cytometry, Cell Counting Kit 8 (CCK-8), colony formation assays, and in vivo experiments. The mechanism by which RPN1 modifies programmed death ligand-1 (PD-L1) and the tumor microenvironment was examined by RT-qPCR, western blotting, co-immunoprecipitation (Co-IP), and flow cytometry. The influence of the transcription factor YY1 on RPN1 expression was revealed using bioinformatics analysis, RT-qPCR, and dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RPN1 is aberrantly expressed in triple-negative breast cancer (TNBC) cells, correlating with increased proliferation and poor prognosis. RPN1 mediates the post-translational modification of PD-L1, enhancing its glycosylation and stability, thus facilitating PD-L1-mediated immune escape and tumor growth. The deletion of RPN1 improves the TNBC microenvironment and enhances the efficacy of anti-PD-1 therapy. Additionally, we uncovered a novel regulatory axis involving YY1/RPN1/YBX1 in PD-L1 regulation, affecting TNBC growth and metastasis. Our preliminary study reveals that targeting RPN1 promotes immune suppression, providing a new potential immunotherapy strategy for TNBC. However, further research is necessary to fully elucidate and understand the specific mechanisms of RPN1 in TNBC and its potential for clinical application .

Prognostic significance of programmed death ligand 2 expression in tumor-infiltrating lymphocytes of triple-negative breast cancer

Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and overexpression of human epidermal growth factor receptor 2 protein. Patients with high expression of programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been found to have better prognosis and increased response to anti-PD-1/PDL1 immunotherapy. However, the role programmed death ligand 2 (PD-L2), the other known ligand of PD-1, plays in PD-1/PD-L1 checkpoint pathway has not been well studied. Therefore, this project aims to investigate (1) the relationship between PD-L2 expression in tumor infiltrating lymphocytes (TILs) and patient clinicopathological features, (2) whether PD-L2 can serve as a predictor of patient survival, and (3) the association of PD-L2 expression with the infiltration of relevant immune cell types in the tumor microenvironment. Materials and Methods: Two hundred and ninety-six (296) TNBC cases diagnosed between 2003 and 2013 in Singapore General Hospital were used in this study to create tissue microarray for immunohistochemistry with several antibodies. Results: Patients with PD-L2 expression were found to have significantly improved disease-free survival (hazard ratio [HR] 0.51; P = 0.0362) and overall survival (HR 0.43; P = 0.0379) compared to patients who have negative PD-L2 expression. PD-L2+ TILs correlate significantly with CD3+ T-cells (P = 0.00776) and CD20+ B-cells (P = 0.001019) infiltration in the stromal compartments and intratumoral CD38+ plasma cells (P = 0.048869) infiltration. Conclusion: Like PD-L1, PD-L2 positivity in TILs was found in our study to indicate a better prognosis compared to PD-L2-negative patients.

Whole slide imaging of tumour microenvironment in classical Hodgkin’s lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells

AimsThe prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined.MethodsModel development via Transparent Reporting of a multivariable prediction model for Individual Prognosis...

Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study

BackgroundRecent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.MethodsIn this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.ResultsThis study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1–4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high “ABC transporters” signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.ConclusionsAdding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1–4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.

Research progress of immune checkpoint inhibitors in ovarian cancer

Ovarian cancer is the deadliest malignant tumor in the female reproductive system. Despite advancements in standard treatments such as tumor debulking surgery and platinum-based chemotherapy, the overall survival rate remains low. The emergence of targeted therapies, including Poly(ADP-ribose) polymerase (PARP) inhibitors and anti-angiogenic agents, has provided new avenues for treatment. However, drug resistance and disease heterogeneity continue to pose significant challenges. Immune checkpoint inhibitors (ICIs), as an emerging therapeutic approach, primarily target the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways to restore anti-tumor immune responses. Although ICIs have shown significant efficacy in other malignancies, their effectiveness in ovarian cancer is limited, with a response rate of only 10–15% for monotherapy. Recent studies have focused on combining ICIs with chemotherapy, anti-angiogenic agents, or PARP inhibitors to enhance therapeutic outcomes. This article reviews the progress of ICIs in ovarian cancer, including monotherapy and combination treatment strategies, and explores emerging therapeutic targets and strategies aimed at improving patient prognosis and achieving personalized treatment. By gaining a deeper understanding of the tumor microenvironment and its immune evasion mechanisms, there is hope for developing more effective treatment options in the future, ultimately improving the survival rates and quality of life for ovarian cancer patients.

Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by enhancing interferon-γ-induced chemokines in tumor cells.

Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11.

CXCL12 restricts tumor growth by suppressing the Ras, ERK1/2, c-Myc, and the immune checkpoint PD-L1 pathways

Cytokines constitute a family of proteins that modulate the immune system and are secreted by many cells. CXCL12, along with its receptor CXCR4, are essential players in numerous processes. Dysregulation of their function underlie the mechanism(s) of several pathologies, including malignancies. Here, we demonstrate an unexpected effect of the cytokine and its receptor: In both cells and animal models, CXCL12 restricts tumorigenicity of the human glioblastoma cells U87-MG and U-118, and of a cell line derived from PyMT mouse breast cancer. Overexpression of CXCL12 inhibits activation of the oncogene Ras which results in downregulation of its proliferative signals, such as reduced phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), inhibition of c-Myc expression, and subsequent inhibition of cell cycle. Furthermore, CXCL12 induces downregulation of the growth differentiation factor 15 (GDF15), insulin-like growth factor-binding protein 6 (IGFBP6), and matrix metalloproteinase-3 (MMP3), which are implicated in sending metastases. Indeed, monitoring cell migration in vitro and generation of metastases in mice demonstrate that CXCL12 slows the migration of U87-MG and PyMT cells. Remarkably, overexpression of CXCL12 also downregulates the cell surface immune checkpoint protein programmed cell death-ligand 1 (PD-L1), resulting in recruitment of cytotoxic CD8 T cells into xenografts accompanied by their shrinkage. Overall, CXCL12 inhibits tumor growth through several distinct mechanisms: inhibition of cell cycle and migration, as well as impairment of immune checkpoint, thereby stimulating a strong host's immune response. The mechanism(s) that renders CXCL12 a tumor-promoting factor in certain cells and a suppressor in others has remained elusive.

Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.

This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.