Programmed Death-1 Research Articles

TLS and immune cell profiling: immunomodulatory effects of immunochemotherapy on tumor microenvironment in resectable stage III NSCLC

BackgroundThe use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.MethodsThis study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.ResultsPatients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.ConclusionsImmunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.

Consolidation immunotherapy following concurrent chemoradiotherapy in a patient with sinonasal NUT carcinoma: a case report

BackgroundNuclear protein in testis (NUT) cancers, also known as midline cancers, tends to occur in organs near the midline, such as the nasal sinuses and mediastinum. NUT carcinoma is very rare and has a poor prognosis.Case descriptionWe report the case of a 44-year-old female patient with sinonasal NUT carcinoma who presented with a soft tissue mass in the left frontal sinus, ethmoid sinus, and left nasal cavity on computed tomography; the tumor was poorly demarcated from the left rectus medialis. After discussion with a multidisciplinary team with expertise on head and neck tumors, the patient was considered inoperable, and definitive concurrent chemoradiotherapy (CCRT) was recommended. The patient underwent CCRT followed by three cycles of consolidation chemotherapy with albumin-bound paclitaxel and nedaplatin. Subsequently, the patient underwent 16 cycles of consolidation therapy with the programmed death–1 (PD-1) inhibitor tislelizumab. The immune-related adverse events included grade 2 hypothyroidism. After CCRT, consolidation chemotherapy, and consolidation immunotherapy, the patient achieved a favorable outcome. The patient survived for 31 months, and there were no signs of recurrence or metastasis during follow-up.ConclusionAt present, there is no clear consensus on the consolidation treatment plan after CCRT for sinonasal NUT cancer. We used consolidation immunotherapy for the first time and achieved good efficacy, providing an innovative and promising treatment plan for refractory sinonasal NUT cancer.

Consensus on immunotherapy for small cell lung cancer(2024 edition)

Lung cancer is one of the malignant tumors with high morbidity and mortality worldwide. Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is closely associated with tobacco exposure, accounting for 13% to 15% of all lung cancer cases. It is characterized by a high proliferation rate and exceptional metastatic capacity. At the time of diagnosis, approximately 70% of the patients have metastasized and are classified as extensive-stage small cell lung cancer (ES-SCLC). From 1980 to 2018, chemotherapy and radiotherapy were the main treatment strategies for SCLC. Etoposide combined with platinum has remained the standard first-line treatment for ES-SCLC. Although SCLC is very sensitive to initial treatment, the majority of patients have disease progression within 6 months, and treatment options after recurrence are very limited, and the median survival time is only about 8-10 months. The advent of immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) and programmed death -1 (PD-1) inhibitors, has brought new hope to patients with SCLC. PD-1/PD-L1 plus chemotherapy have significantly prolonged overall survival of patients with ES-SCLC, which has become the new standard of first-line treatment for ES-SCLC. Currently, a raised number of immune checkpoint inhibitors (ICIs) have been approved in China for the treatment of SCLC, providing more treatment options for SCLC patients. To further standardize the clinical practice of SCLC immunotherapy, the "Expert Consensus on Immunotherapy for SCLC" has been developed based on domestic and international guidelines, consensus, and relevant medical evidence, aiming to provide reference and guidance for domestic clinicians.

Regorafenib Combination Therapy in Advanced Hepatocellular Carcinoma: With or Without Transarterial Chemoembolization.

The effectiveness and tolerability of triple therapy, which combines regorafenib, a programmed death 1 (PD-1) inhibitor, and transarterial chemoembolization (TACE), were compared to dual therapy consisting of regorafenib and a PD-1 inhibitor in patients with advanced hepatocellular carcinoma (HCC). A retrospective analysis was conducted on patients with advanced HCC who underwent second-line therapy from March 2019 to June 2022 at multiple centers. Patients were stratified into two groups: dual therapy (comprising regorafenib and a PD-1 inhibitor) and triple therapy (consisting of regorafenib, a PD-1 inhibitor, and TACE). Propensity score matching (PSM) was used to control for potential confounding variables. After PSM, 112 eligible patients were included, with 56 in the triple therapy group and 56 in the dual therapy group. Median overall survival (OS) was significantly longer in the triple therapy group (15.4 vs. 8.9 months, p < 0.001), as was median progression-free survival (PFS) (6.8 vs. 3.3 months, p < 0.001). The objective response rate (ORR) (37.5% vs. 5.4%, p < 0.001) and disease control rate (DCR) (73.2% vs. 44.6%, p = 0.002) were significantly higher in the triple therapy group compared to the dual therapy group. The incidence and severity of adverse events were similar between the two groups. Triple therapy demonstrated superior survival benefits compared to dual therapy in patients with advanced HCC. Additionally, the safety profiles of the two treatment regimens were comparable.

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.

Role of PD-1 in modulating IFN-γ-CXCL9/10-CXCR3 signaling in breast cancer.

Breast cancer represents a significant health burden globally, necessitating ongoing advancements in treatment strategies for improved patient outcomes. Immunotherapy, particularly targeting immune checkpoints like programmed death-1 (PD-1), has emerged as a promising approach in cancer therapy. This study focuses on elucidating the role of PD-1 in modulating the IFN-γ-CXCL9/10-CXCR3 signaling axis within the breast cancer microenvironment. By investigating the synergistic effects of PD-1 inhibitors in combination with Inetetamab, our research aims to uncover novel therapeutic targets for enhancing immunotherapy efficacy in breast cancer. Through comprehensive experimental analysis, we seek to deepen our understanding of the intricate molecular mechanisms underlying immune regulation in breast cancer, thereby paving the way for more effective and sustainable treatment strategies. Ultimately, our study endeavors to establish a robust theoretical framework that can guide the development of innovative clinical interventions, aiming for improved outcomes in breast cancer patients.

The Potential of PD-1 and PD-L1 as Prognostic and Predictive Biomarkers in Colorectal Adenocarcinoma Based on TILs Grading

Aim: Colorectal cancer (CRC) is a prevalent malignancy with a high mortality rate. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the immune response against tumors. Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are key immune checkpoints regulating T cells in the tumor microenvironment. This study aimed to assess the relationships among PD-1 expression on TILs, PD-L1 expression in tumors, and TIL grading in colorectal adenocarcinoma. Methods: A cross-sectional design was employed to analyze 130 colorectal adenocarcinoma samples. The expression of PD-1 and PD-L1 was assessed through immunohistochemistry. A semi-quantitative scoring system was applied. Statistical analysis with the chi-square test was performed to explore correlations, with the data analyzed in SPSS version 27. Results: PD-1 expression on TILs significantly correlated with a higher TIL grading (p &lt; 0.001), while PD-L1 expression in tumors showed an inverse correlation with TIL grading (p &lt; 0.001). Conclusions: The expression of PD-1 on TILs and PD-L1 on tumor cells correlated significantly with the grading of TILs in colorectal adenocarcinoma. This finding shows potential as a predictive biomarker for PD-1/PD-L1 blockade therapy. Further studies are needed to strengthen these results.

Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab.

We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate. OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group. Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearancesignificantlydecreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells. OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

Immunophenotypic Profile of Adult Glioblastoma IDH-Wildtype Microenvironment: A Cohort Study.

Background: Glioblastoma IDH-wildtype (GBM IDH-wt) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping its tumor microenvironment (TME) regulate tumor progression and treatment response. The aim of this study was to characterize the main immunosuppressive elements of the GBM IDH-wt TME. Methods: Immunohistochemistry for CD3, CD4, CD8, CD163, programmed death ligand 1 (PD-L1) and programmed death 1 (PD1) was performed on surgical tumor specimens from patients diagnosed with GBM IDH-wt, according to the CNS WHO 2021 criteria. The impact of categorical variables on time-dependent outcomes such as overall survival (OS) and progression-free survival (PFS) has been estimated through the Kaplan-Meier method. Results: We included 30 patients (19 males and 11 females), median age of 59.8 years (range 40.2-69.1 years). All patients underwent surgery followed by temozolomide concurrent with and adjuvant to radiotherapy. MGMT was methylated in 14 patients (47%) and unmethylated in 16 patients (53%). The overall absolute percentages of CD4+ lymphocytes, both intratumoral and perivascular, were significantly more represented than CD8+ lymphocytes in the TME (p = 0.02). A low density of CD4+ lymphocytes (≤10%) was found to be a favorable prognostic factor for GBM outcome (p = 0.02). Patients with MGMT methylated and unmethylated tumors exhibited a distinct TME composition, with a significant higher number of perivascular CD8+ lymphocytes (p = 0.002), intratumoral CD8+ lymphocytes (p = 0.0024) and perivascular CD4+ lymphocytes (p = 0.014) in MGMT unmethylated tumors. PD-L1 expression in tumor cell surface was observed in four tumors (13.3%), and PD1 expression in infiltrating T lymphocytes was observed in nine (30%) tumors, with predominantly perivascular distribution. Conclusions: MGMT methylated and unmethylated tumors exhibit different immune profiles, likely reflecting the different biology of these tumors. The expression of PD-L1 in GBM IDH-wt patients is confined to a small subpopulation. While we found a significant association between low CD4+ lymphocyte density (≤10%) and survival, given the small numbers of our cohort, the prognostic value of CD4+ lymphocyte density will need to be validated in large-scale studies.

Implications of glioblastoma-derived exosomes in modifying the immune system: state-of-the-art and challenges.

Glioblastoma is a brain cancer with a poor prognosis. Failure of classical chemotherapy and surgical treatments indicates that new therapeutic approaches are needed. Among cell-free options, exosomes are versatile extracellular vesicles (EVs) that carry important cargo across barriers suchas the blood-brain barrier (BBB) to their target cells. Thismakes exosomes an interesting option for the treatment ofglioblastoma. Moreover, exosomes can comprise many therapeutic cargos, including lipids, proteins, and nucleic acids,sampled from special intercellular compartments of their origin cell. Cells exposed to various immunomodulatory stimulican generate exosomes enriched in specific therapeutic molecules. Notably, the secretion of exosomes could modify theimmune response in innate and adaptive immune systems. For instance, glioblastoma-associated exosomes (GBex) uptake bymacrophages could influence macrophage dynamics (e.g., shifting CD markers expression). Expression of critical immunoregulatory proteins such as cytotoxic T-lymphocyte antigen-1 (CTLA1) and programmed death-1 (PD-1) on GBex indicates the direct crosstalk of these nano-size vesicles with the immune system. The present study reviews the role of exosomes in immune system cells, including Bcells, Tcells, natural killer (NK) cells, and dendritic cells (DCs), as well as novel technologies in the field.

The unexpected PD-L1 suppression function of celery-derived extracellular vesicles improves lung cancer chemotherapy efficacy

Aim: The article explores celery-derived extracellular vesicles (CDEVs), characterized by high cellular uptake, low immunogenicity, and high stability, as a therapeutic strategy for antitumor nanomedicines. Methods: The methods employed in this study include in vitro cell experiments such as co-culture, Western Blot, and flow cytometry. In vivo experiments were conducted in C57BL/6 tumor-bearing mice subcutaneously injected with Lewis lung carcinoma (LLC) cells. The experiments encompassed parameters such as survival rate, body weight, tumor size, flow cytometry, immunohistochemistry, and spectral live imaging system. Results: Our study revealed that CDEVs could be used as drugs to effectively downregulate the phosphorylated signal transducer and activator of transcription 3(p-STAT3)/programmed cell death ligand 1 (PD-L1) axis in lung cancer cells. In co-culture experiments, CDEVs were observed to impede the expression of PD-L1, thereby interfering with the interaction between PD-L1 and programmed death 1 (PD-1) and subsequently preventing the suppression of T cells. In in vivo distribution experiments, CDEVs loaded with paclitaxel (PTX) demonstrated better tumor targeting capabilities. Remarkably, following CDEVs-PTX treatment, CD8+ T cell levels in mice were increased, presumably leading to improved antitumor effects. Conclusion: CDEVs not only serve as drug carriers but also function as drugs themselves; as such, through a single administration of CDEVs, it is possible to combine immunotherapy and chemotherapy to achieve better effects between the two, providing a more comprehensive and effective cancer treatment strategy that promises to improve treatment outcomes and reduce the adverse effects of therapy.

The role of PD-1/PD-L1 pathway in ulcerative colitis and changes following tonsil-derived mesenchymal stem cells treatment.

The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has not been fully evaluated in inflammatory bowel disease. We evaluated PD-1/PD-L1 levels in patients with ulcerative colitis (UC) and their significance in tonsil-derived mesenchymal stem cells (TMSCs) treatment. Using acute and chronic murine colitis model, we measured the PD-1 and PD-L1 levels in inflamed colonic tissues pre- and post-treatment with TMSCs. We also measured PD-1 and PD-L1 levels in colonic tissues from UC patients, compared to normal controls. In the analysis using human colonic tissues, a significant increase in the levels of PD-1 and PD-L1 was observed in the colonic mucosa of patients with UC compared with normal controls (p < 0.001 and p = 0.005, respectively). When comparing the maximal disease extent, PD-L1 levels were highest in patients with proctitis (38.5 ± 46.7), followed by left-side colitis (17.5 ± 23.1) and extensive colitis (5.2 ± 8.2) (p < 0.001). In the chronic colitis model, the level of PD-L1 was decreased (p = 0.040) and the level of PD-1 increased more than in normal controls (p = 0.047). After treatment with TMSC, significant improvements were observed in body weight, disease activity index, and colon length recovery. Additionally, the levels of PD-1 and PD-L1 were recovered; PD-L1 significantly increased (p = 0.031), while the level of PD-1 decreased (p = 0.310). The altered expression of PD-1 and PD-L1 in colonic mucosa may be a possible mechanism of UC, and T-MSC-derived PD-L1 could help suppress colitis.

Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases

Background Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic...

The Potential Role of Toxoplasma Gondii Infection in Breast Cancer Through Affecting Programmed Death-1 Genes

Background: This study aimed to evaluate the possible effects of Toxoplasma gondii infection on breast cancer through affecting the serum and expression gene level of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer patients from Thi-qar province, Iraq. Methods: This case-control study was involved 150 patients suffering from breast cancer (BC) who were referring to general hospitals of Thi-Qar province between July to September 2023 and 150 healthy patients (non-BC). Enzyme-linked immunosorbent test (ELISA) kit was used to evaluate the anti-Toxoplasma IgG and the serum level of PD-1 and PDL-1. Furthermore, the expression level of PD-1 and PDL-1 was measured through Real-time PCR. Results: Among 150 breast cancer patients, 71 patients (47.3%) and 25 (16.6%) of healthy subjects exhibited seropositivity for anti-T. gondii IgG antibodies, resepectively. We found that the serum level and the gene expression level of PD-1 and PDL-1 were significantly higher among BC patients seropositive for T. gondii compared with BC patients who were seronegative for T. gondii antibodies (p&lt;0.05). Conclusion: These results indicated that T. gondii may play a role in the occurrence and even progression of cancer probably by elevating levels of PD-1 and PDL-1 genes. However, further studies are required to confirm these findings.

Identification of lncRNA dual targeting PD-L1 and PD-L2 as a novel prognostic predictor for gastric cancer.

Although breakthroughs have been achieved in gastric cancer (GC) therapy with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), the acquisition of high response rate remains a huge challenge for clinicians. It is imperative to identify novel biomarkers for predicting response to immunotherapy and explore alternative therapeutic strategy for GC. The transcriptomic profiles and clinical information of GC patients from The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) database was used to screen differentially expressed lncRNAs between the tumor specimens and the paracancerous tissues. The TargetScan, miRDB and miRcode database were then utilized to construct competing endogenous RNA (ceRNA) networks and identify pivotal lncRNAs. An independent dataset from GEO (GSE70880) and 23 pairs of GC specimens of our cohort were subsequently performed for external validity. The relationship between clinical variables and gene expression were evaluated by Kruskal-wallis test and Wilcoxon signed-rank. The prognostic value of the candidate genes was assessed using Kaplan-Meier analysis and Cox regression models. CIBERSORT and Gene set enrichment analysis (GSEA) were used to determine immune cell infiltration. Gastric adenocarcinoma AGS cells and human embryonic kidney 293T (HEK293T) cells with knockdown of LINC01094 were generated by siRNA transfection, followed by detecting the alteration of the target miRNA and PD-L1/PD-L2 by RT-qPCR. Besides, the interaction between lncRNA and the miRNA-PD-L1/PD-L2 axis were verified by dual luciferase reporter assay. Twenty-two intersecting lncRNAs were identified to be PD-L1/PD-L2-related lncRNAs and LINC01094-miR-17-5p-PD-L1/PD-L2 was constructed as a potential ceRNA network. LINC01094 was increased in tumor specimens than adjacent normal samples and was positively associated with advanced tumor stages and EBV and MSI status. Furthermore, LINC01094 expression was an independent risk factor for poor overall survival (OS) in GC patients. CD8+ T cell exhaustion-related genes were enriched in high-LINC01094 tissues and high-PD-L2 group. A strong positive association of LINC01094 expression was established with M2 macrophages, IL-10+ TAM, as well as PD-L1 and PD-L2 levels, therefore a LINC01094-miR-17-5p-IL-10 network was proposed in macrophages. Using the exoRBase database, LINC01094 was assumed in blood exosomes of GC patients The results of knockdown experiments and luciferase reporter assays revealed that LINC01094 interacted with miR-17-5p and served as a miRNA sponge to regulate the expression of PD-L1 and PD-L2. LINC01094 dually regulates the expression of PD-L1 and PD-L2 and shapes the immunosuppressive tumor microenvironment via sponging miR-17-5p. LINC01094 may serve as a potential prognostic predictor and therapeutic target in GC.

Cancer new treatment series: Comparison immune changes of HCC by scRNA-Seq following HELC treatment one case study

Immunotherapy has emerged as a novel treatment strategy for many types of cancers, among them, liver cancer. The major advances and achievements in recent years is the use of programmed death-1 (PD-1) blockers for cancer treatment. Since patients’ immune systems are already weak following concurrent surgery plus chemo or radiotherapy, it is necessary to restore and awake their immune cells to maximize the effect for immune therapy. Methods: Liver cancers were treated twice with hapten enhanced local chemotherapy (HELC) like tumor lysates vaccine and following PD-1. Single-cell RNA sequencing (scRNA-seq) was used to analyze the changes of immune responses prior and after treatments. Results: We observed upregulation of cytotoxicity-related genes of CD8 effector T cells and NK cells in untreated tumor; Both Bmem and Naive B cells in untreated tumor showed a significant increase in MHC II signaling pathway-related genes, while MHC I-related genes was upregulated in plasma cells. Significant tumor size shrinkage was observed in both treated and untreated tumors following the HELC+PD-1 therapy. Conclusions: This study provides new biological insights into the abscopal effect at the single-cell level related to the composition of T and B cells in untreated liver cancers before and after major primary tumors treated by HELC. Our data showed that intra-tumor HELC can kill tumor cells and induced immune activity, which is likely vital in modifying tumor associate antigens (TAAs) into neo TAAs. It induces immune response just like vaccine can wake up immune cells and therefore increasing the efficacy of PD1 therapy.

Construction and validation of a prognostic model based on immune-metabolic-related genes in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC), a significant type of head and neck cancer, has witnessed increasing incidence and mortality rates. Immune-related genes (IRGs) and metabolic-related genes (MRGs) play essential roles in the pathogenesis, metastasis, and progression of OSCC. This study exploited data from The Cancer Genome Atlas (TCGA) to identify IRGs and MRGs related to OSCC through differential analysis. Univariate Cox analysis was utilized to determine immune-metabolic-related genes (IMRGs) associated with patient prognosis. A prognostic model for OSCC was constructed using Lasso-Cox regression and subsequently validated with datasets from the Gene Expression Omnibus (GEO). Non-Negative Matrix Factorization (NMF) clustering identified three molecular subtypes of OSCC, among which the C2 subtype showed better overall survival (OS) and progression-free survival (PFS). A prognostic model based on nine IMRGs was developed to categorize OSCC patients into high- and low-risk groups, with the low-risk group demonstrating significantly longer OS in both training and testing cohorts. The model showed strong predictive capabilities, and the risk score served as an independent prognostic factor. Additionally, expression levels of programmed death 1 (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) differed between the risk groups. Gene Set Enrichment Analysis (GSEA) indicated distinct enriched pathways between high-risk and low-risk groups, highlighting the crucial roles of immune and metabolic processes in OSCC. The nine IMRGs prognostic model presented excellent predictive performance and has potential for clinical application.

Continuation of same programmed death-1 inhibitor regime beyond progression is a novel option for advanced gastric cancer

BackgroundGastric cancer is a significant global malignancy with poor prognosis. Although the emergence of immune checkpoint inhibitors (ICIs) prolonged the duration of survival, resistance and progression are inevitable. We aim to evaluate the effectiveness of programmed death-1 (PD-1) inhibitors in immunotherapy beyond progression (IBP).MethodWe divided the advanced gastric cancer patients who received two lines immunotherapy into same regimen group (with same PD-1 inhibitor regime after IBP) and different regimen group (with different PD-1 inhibitor regime after IBP). Statistical analysis conducted to compare patient characteristics and evaluate survival differences between groups.ResultThe clinical outcome analysis showed that the same PD-1 inhibitor regime seemed to exhibit a higher disease control rate (DCR) (51.8% vs. 29.2%, P = 0.062), significantly prolonged progression-free survival 2 (PFS2) (162 vs. 75 days, P = 0.001) and overall survival (OS) (312 vs. 166 days, P = 0.022) when compared with those of cross line. In the multivariate analysis, when using different regimen group as reference, the same regimen group was found to be independently associated with improved PFS2 [hazard ratio (HR) = 0.467, 95% confidence interval (CI): 0.267–0.816, P = 0.008] and OS (HR = 0.508, 95%CI: 0.278–0.927, P = 0.027).ConclusionContinuation of the same type of PD-1 inhibitor regime in IBP shows clinical benefits and represents a promising therapeutic approach.

Shedding light on cancer immunology at the molecular level: A quantum biochemistry study of representative PD-1/PD-L1 conformations

BackgroundProgrammed death 1 (PD-1) binding to PD-L1 is a potent mechanism used by immunogenic tumors to evade the immune system and the immune checkpoint PD-1PD-L1 has emerged as a promising target in the search for new drugs to improve cancer treatment. The crystallographic structure of humanPD-1humanPD-L1 shed light on the molecular characterization of this system and allowed computational studies to be carried out to characterize structural behaviors. MethodsThis study demonstrated the importance of analyzing the flexibility of protein systems through molecular dynamics simulations (MDS) and its impacts on the interaction energy obtained through quantum biochemistry. ResultsThe computational results obtained provide a description of the flexibility and energetic profile of the PD-1PD-L1 contact surface using representative conformations from MDS. Variations of up to 50 % in the total interaction energy values were detected depending on the scrutinized conformation, which can be mainly attributed to the flexibility of the CC' loop, FG loop and ASP85-GLN91 of PD-1 and the MET58-LYS62 segment of PD-L1. Quantum biochemistry revealed the three hot spots in PD-L1: ARG113L-ARG125L > ILE54L-VAL76L > ALA18L-ASP26L; and two energetic hot spots in PD-1: ALA125-ARG139 > VAL63-GLN88. Nonetheless, VAL63-GLN88 and GLY124-ARG139 exhibit significant variation in interaction energy between different conformations, while ARG113L-ARG125L is the only hot spot with high energetic fluctuation on the PD-L1 surface. ConclusionThis is the first application of MDS coupled to dimensionality reduction and density functional theory (DFT) demonstrating new structural and energetic features that might be useful in discovering/designing more potent PD-1PD-L1 inhibitors.

Siglec-G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy.

CD8+ T cells play a critical role in cancer immune-surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 (Tim-3). Here Siglec-G is identified as a coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec-G-SHP2 axis in CD8+ T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec-G in inhibiting CD8+ T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.