Search Results (341)

Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-γ from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-α/β, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy. Full article

Glucocorticoids (GCs), such as dexamethasone (DEX), are commonly administered to glioblastoma (GBM) patients to control cerebral edema; however, their effects on immune checkpoint regulation in tumor cells remain insufficiently characterized. This study examined the impact of DEX on the expression of programmed death-ligand 1 (PD-L1) and glucocorticoid-induced leucine zipper (GILZ), a downstream effector of glucocorticoid receptor (GR) signaling, in the U87 and U251 glioblastoma cell lines. DEX consistently induced GILZ expression in both models yet elicited divergent effects on PD-L1: suppression in U87 cells and upregulation in U251 cells. In U87 cells, DEX-induced PD-L1 downregulation was accompanied by accelerated cell cycle progression, suggesting a dual impact on tumor immune evasion and proliferation. Mechanistically, GILZ silencing restored ERK phosphorylation and reversed PD-L1 suppression, whereas GILZ overexpression further decreased PD-L1 levels, implicating a GILZ–ERK pathway in the control of PD-L1. These findings uncover a previously unrecognized GR–GILZ–PD-L1 regulatory axis in glioblastoma cells. While these results are based on in vitro models, they provide a rationale for future in vivo studies to determine whether modulation of GILZ may influence immune checkpoint dynamics and therapeutic responsiveness in GBM. Full article

Tumor immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and eliminate malignant cells, with immune checkpoint inhibitors targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) demonstrating remarkable clinical success. However, challenges such as treatment resistance, immune-related adverse effects, and high costs highlight the need for novel therapeutic approaches. Aptamers, short, single-stranded oligonucleotides with high specificity and affinity for target molecules, have emerged as promising alternatives to conventional antibody-based therapies. This review provides a comprehensive analysis of aptamer-based strategies targeting immune checkpoints, with a particular focus on PD-1/PD-L1 and CTLA-4. We summarize recent advances in aptamer design, including bispecific and multifunctional aptamers, and explore their potential in overcoming immune resistance and improving therapeutic efficacy. Additionally, we discuss strategies to enhance aptamer stability, bioavailability, and tumor penetration through chemical modifications and nanoparticle conjugation. Preclinical and early clinical studies have demonstrated that aptamers can effectively block immune checkpoint pathways, restore T-cell activity, and synergize with other immunotherapeutic agents to achieve superior anti-tumor responses. By systematically reviewing the current research landscape and identifying key challenges, this review aims to provide valuable insights into the future directions of aptamer-based cancer immunotherapy, paving the way for more effective and personalized treatment strategies. Full article

The interaction of programmed cell death receptor 1 (PD-1) on the surface of immune cells with its ligand, programmed cell death ligand 1 (PD-L1), expressed on tumour cells and antigen-presenting cells, leads to tumour immune evasion. Antibodies that target either PD-1 or its ligand PD-L1 have shown a favourable response in cancer patients, especially those with non-small cell lung cancer (NSCLC). However, only 15 to 25% of advanced NSCLC patients will benefit from immunotherapy. The PD-L1 tumour proportion score (TPS) is the current standard biomarker to select patients for PD-1/PD-L1 blockade therapy, as patients with a high PD-L1 TPS show better response compared to patients with a low PD-L1 TPS. However, since PD-L1 expression is a continuous variable and is an imperfect biomarker, investigation into additional predictive markers is warranted. This review focuses on tumour- and non-tumour-associated factors that have been shown to affect the response to PD-1/PD-L1 inhibitors in NSCLC. We also delve into mechanistic and clinical evidence on these potential biomarkers and their relationship to the tumour microenvironment (TME). Full article

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) 4 alone or in combination with other drugs, has led to unexpected positive results in some tumors but not all. Several other molecules inhibiting lymphocyte antitumor effector subsets have been discovered in the last 30 years. Herein, we focus on the leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1/CD305). LAIR1 represents a typical immunoregulatory molecule expressed on almost all leukocytes, unlike other regulatory receptors expressed on discrete leukocyte subsets. It bears two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the intracytoplasmic protein domain involved in the downregulation of signals mediated by activating receptors. LAIR1 binds to several ligands, such as collagen I and III, complement component 1Q, surfactant protein D, adiponectin, and repetitive interspersed families of polypeptides expressed by erythrocytes infected with Plasmodium malariae. This would suggest LAIR1 involvement in several cell-to-cell interactions and possibly in metabolic regulation. The presence of both cellular and soluble forms of LAIR would indicate a fine regulation of the immunoregulatory activity, as happens for the soluble/exosome-associated forms of PD1 and CTLA4 molecules. As a consequence, LAIR1 appears to play a role in some autoimmune diseases and the immune response against tumor cells. The finding of LAIR1 expression on hematological malignancies, but also on some solid tumors, could open a rationale for the targeting of this molecule to treat neoplasia, either alone or in combination with other therapeutic options. Full article

Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics^® BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC. Full article

The combination of immunotherapy and radiotherapy has demonstrated synergistic potential, especially when a combination of immune checkpoint inhibitors (ICIs) is administered. Cytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors or Programmed Cell Death Protein 1 (PD-1) inhibitors have been assessed in both clinical and preclinical studies; the addition of radiotherapy activates immunomodulatory mechanisms materialized by an effect similar to “in situ” vaccination or the “abscopal” distant response of lesions outside the irradiation field. The new therapeutic targets (T cell immune-receptor with Ig and ITIM domains (TIGIT), Lymphocyte activating gene 3 (LAG-3), and T cell Ig- and mucin-domain-containing molecule-3 (TIM-3)) associated with traditional ICIs and radiotherapy open new perspectives to the concept of immuno-radiotherapy. The dynamic evaluation of T lymphocyte expression involved in the antitumor immune response, both in the tumor microenvironment (TME) and in the tumor itself, could have biomarker value in assessing the response to combination therapy with traditional and new ICIs in association with irradiation. Preclinical data justify the initiation of clinical trials in various tumor pathologies to explore this concept. Full article

The insertion of a transgene downstream of the L3-23K or L5-Fiber region was reported as a vital strategy for arming E3 non-deleted oncolytic adenoviruses. However, depending on the percentage of codons with G/C at the third base position (GC3%) and the type of splicing acceptor, an insert downstream of the L5-Fiber region may substantially affect virus fitness. Since the insertion of transgenes downstream of the L3-23K and L5-Fiber regions has never been compared in terms of their expression levels and impact on virus fitness, we assessed the total virus yield, cytolytic efficacy, and plaque size of Ad5-delta-24-RGD (Ad5Δ24RGD) armed with EGFP, FLuc, the suppressor of RNA silencing p19, soluble wild-type human/mouse and high-affinity human programmed cell death receptor-1 (PD-1/PDCD1) ectodomains, and soluble human hyaluronidase PH20/SPAM1. The insertion of transgenes downstream of the L3-23K region ensures their production at considerably higher levels. However, the insertion of transgenes downstream of either region differentially and unpredictably affects the oncolytic potency of Ad5Δ24RGD, which cannot be explained by GC3% or expression level alone. Surprisingly, the expression of the human and mouse PD-1 ectodomains with 83.1% and 70.1% GC3%, respectively, does not affect cytolytic efficacy but increases the plaque size in a cell line-dependent manner. Full article

The advent of immune checkpoint blockade (ICB) has transformed cancer immunotherapy, enabling remarkable long-term outcomes and improved survival, particularly with ICB combination treatments. However, clinical benefits remain confined to a subset of patients, and life-threatening immune-related adverse effects pose a significant challenge. This limited efficacy is attributed to cancer heterogeneity, which is mediated by ligand–receptor interactions, exosomes, secreted factors, and key transcription factors. Oncogenic regulators like E2F1 and MYC drive metastatic tumor environments and intertwine with immunoregulatory pathways, impairing T cell function and reducing immunotherapy effectiveness. To address these challenges, FDA-approved biomarkers, such as tumor mutational burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression, help to identify patients most likely to benefit from ICB. Yet, current biomarkers have limitations, making treatment decisions difficult. Recently, T cells—the primary target of ICB—have emerged as promising biomarkers. This review explores the relationship between cancer drivers and immune response, and emphasizes the role of CD8+ T cells in predicting and monitoring ICB efficacy. Tumor-infiltrating CD8+ T cells correlate with positive clinical outcomes in many cancers, yet obtaining tumor tissue remains complex, limiting its practical use. Conversely, circulating T cell subsets are more accessible and have shown promise as predictive biomarkers. Specifically, memory and progenitor exhausted T cells are associated with favorable immunotherapy responses, while terminally exhausted T cells negatively correlate with ICB efficacy. Ultimately, combining biomarkers enhances predictive accuracy, as demonstrated by integrating TMB/PD-L1 expression with CD8+ T cell frequency. Computational models incorporating cancer and immune signatures could further refine patient stratification, advancing personalized immunotherapy. Full article

In the clinical setting, the efficacy of single-agent immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC) remains suboptimal. Therefore, there is a pressing need to develop predictive biomarkers to identify non-responders. Considering that cancer-associated fibroblasts (CAFs) represent an integral component of the tumor microenvironment that affects the stiffness of solid tumors on shear-wave elastography (SWE) imaging, wound healing CAFs (WH CAFs) were identified in highly heterogeneous TNBC. This subtype highly expressed vitronectin (VTN) and constituted the majority of CAFs. Moreover, WH CAFs were negatively correlated with CD8⁺ T cell infiltration levels and influenced tumor proliferation in the Eo771 mouse model. Furthermore, multi-omics analysis validated its role in immunosuppression. In order to non-invasively classify patients as responders or non-responders to ICI monotherapy, a deep learning model was constructed to classify the level of WH CAFs based on SWE imaging. As anticipated, this model effectively distinguished the level of WH CAFs in tumors. Based on the classification of the level of WH CAFs, while tumors with a high level of WH CAFs were found to exhibit a poor response to anti programmed cell death protein 1 (PD-1) monotherapy, they were responsive to the combination of anti-PD-1 and erdafitinib, a selective fibroblast growth factor receptor (FGFR) inhibitor. Overall, these findings establish a reference for a novel non-invasive method for predicting ICI efficacy to guide the selection of TNBC patients for precision treatment in clinical settings. Full article

Combination therapy of chemotherapy and zolbetuximab demonstrated a significant survival benefit compared to chemotherapy alone in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin (CLDN) 18.2–positive metastatic gastric cancer (mGC). Consequently, it has been approved as a standard first-line therapy for these patients. Combination therapy of chemotherapy and immune checkpoint inhibitors (ICIs)—either nivolumab or pembrolizumab—is a standard first-line therapy for patients with HER2-negative mGCs that are positive for programmed death-ligand 1 (PD-L1) expression, as defined by a combined positive score (CPS). Although approximately 13–22% of CLDN-positive mGCs are also CPS-positive, optimal treatment for mGC patients expressing both CLDN and PD-L1 remains undetermined due to the absence of direct comparative studies between zolbetuximab and ICIs. Treatment selection under this condition has become a critical issue. In this review, we discuss the appropriate treatment selection for HER2-negative mGC patients who are double-positive for CLDN 18.2 and PD-L1 based on clinical data and differences in the mechanism of action and safety profile between zolbetuximab and ICI. Full article

Immune checkpoint inhibitors have revolutionized cancer treatment but remain limited by on-target/off-tumor effects that narrow their therapeutic window. Although PD-L1 is mainly expressed by tumor cells, these effects could reduce bloodstream availability and tumor accumulation of PD-L1 inhibitors. Enhancing tumor specificity through bispecific proteins targeting two tumor-associated antigens offers a promising strategy. This study evaluated a bispecific Nanofitin, B10–B11, targeting PD-L1 and EGFR. In vitro, B10–B11 efficiently bound to human A431 and murine CT26 cell lines, validating these models for in vivo studies. Nanofitins’ accumulation in tumors and their anti-tumor efficacy were assessed, respectively, in A431 xenograft and CT26 immunocompetent mouse models. In both experiments, B10–B11 was compared with its albumin binding fused counterpart (B10–B11-ABNF). This study showed that the dual-targeting approach with the bispecific Nanofitin enhanced in vitro PD-L1 neutralization compared to the monomeric form and led to in vivo anti-tumor activity evidenced by reduced tumor growth and increased CD3+ T cells and F4/80+ macrophages in tumors. This activity was further correlated with Nanofitin’s tumor accumulation at 7 h post-injection, which was highest for the B10–B11-ABNF. This study highlights the potential of bispecific Nanofitins, particularly with albumin binding to enable rapid and uniform tumor accumulation of effective PD-L1 immunotherapy. Full article

Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated B cell function in untreated patients with CLL, and we further explored the effects of ex vivo protein kinase C activation on immune checkpoint expression and B cell profiles. Methods: Peripheral blood samples were collected from 21 untreated patients with CLL at King Edward Hospital in South Africa, between 2019 and 2022. B cells were stimulated with phorbol myristate acetate (PMA) and ionomycin. Using flow cytometry, the study explored the levels of B cell subsets and immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression on various B cell subsets. Results: PMA and ionomycin B cell stimulation upregulated PD-1, CTLA-4 and PD-L2 expression on B cell subsets (p < 0.01). As expected, monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 significantly downregulated the CTLA-4 expression of B cell subsets (p < 0.05), while PD-L2 exhibited varied responses in different B cell subsets. Moreover, PD-1 and PD-L1 expression on total B cells significantly declined following their blockage (p < 0.01). In addition, these monoclonal antibodies increased the levels of CD19⁺CD27⁺ B cells (p < 0.0128) and activated CD19⁺CD27⁺ B cells (p < 0.01). Conclusions: Protein kinase C activation on B cells stimulates immune checkpoint expression. The use of monoclonal antibodies on B cells plays a critical role in the B cell function through the reduction in CD38 expressing activated B cells and upregulation of CD19⁺CD27⁺ B cells. Moreover, the monoclonal antibody targeting PD-1, PD-L1 and CTLA-4 are effective in reducing the expression of CTLA-4 on B cell subsets, while PD-1 and PD-L1 blockage may be effective in reducing the expression of these immune checkpoints on total B cells. Full article

Sepsis is a leading cause of death in hospitalized patients. The underlying pathophysiologic mechanisms of sepsis have not been fully elucidated thus far. The receptor of programmed cell death 1 (PD-1) and its ligand (PD-L1), in combination with the Toll-like receptors (TLRs), seem to contribute considerably in systematic responses during sepsis. Investigating the relationship between them and identifying potential target pathways is important in the future management of sepsis, especially in relation to acute lung injury. This study investigated the interactions between TLR-5, -6, and -9 and PD-1/PD-L1 expression in a septic mouse model. Sixty C57BL/6J mice were included and categorized in six study groups. Three sepsis (S) groups (24 h, 48 h, and 72 h) and three sham (Sh) groups (24 h, 48 h, and 72 h) were created. Cecal ligation and puncture (CLP) was utilized to simulate sepsis in the S groups. Hematological analysis and lung tissue histopathological analysis were performed after 24 h, 48 h, and 72 h. Significant decreases in S groups compared to Sh groups in WBC and lymphocyte counts at 24, 48, and 72 h were observed. Significant increases in S groups compared to Sh groups in RBC and monocyte counts, IL-6 and IL-10 levels, alveolar flooding, and alveolar collapse were demonstrated by histopathological analysis. This study suggested a strong correlation between TLR expression and PD-1/PD-L1 up-regulation in lung tissue during sepsis. These molecules, also, seem to contribute to the histopathological changes in lung tissue during sepsis, leading to acute lung injury. Full article

Background: Soft tissue sarcomas (STS) are aggressive cancers that show increasing response to novel targeted-therapies and immune-checkpoint-inhibitors. Despite anecdotal reports of cardiovascular adverse events (AEs) and major adverse cardiovascular events (MACE) potentially hindering their utility, the true cardiotoxic profile of these novel-therapies in STS has been largely understudied. Methods: We assessed the incidence and severity of AEs and MACE of contemporary FDA-approved targeted and immune-based therapies for STS, using data from landmark clinical trials supporting FDA-approval. We also analyzed data from the FDA adverse-event-reporting-system-(FAERS) for FDA-approved STS targeted and immune-based therapies for comparative real-world validation. Results: Overall, 12 clinical trials supporting FDA-approval of STS targeted-therapies and immune-checkpoint-inhibitors, incorporating 1249 patients, were identified. These clinical trials revealed 751 AEs including, hypertension (382, 50.87%), atrial fibrillation (3, 0.40%), myocardial infarction (2, 0.27%), cardiac failure (congestive included) (9, 1.20%), and cardiac failure (heart failure included) (7, 0.93%). Compared to placebo, those treated saw higher MACE (OR: 3.27, p < 0.001). The FAERS data showed 489 reported AEs including hypertension (275, 56.24%), atrial fibrillation (31, 6.34%), myocardial infarction (15, 3.07%), and cardiac failure (congestive included) (30, 6.13%). Programmed death-ligand 1 (PD-L1) inhibitors had the highest probability of AEs (0.65, 1.17), followed by tyrosine kinase inhibitors (0.66, 0.11), tropomyosin receptor kinase inhibitors (0.25, 0.13), mammalian target of rapamycin inhibitors (0.21, 0.09), and enhancer of zeste homologue 2 inhibitors (0.11, 0.06). Proportions were calculated from the samples in clinical trials supporting FDA-approval and FAERS, respectively. Conclusions: In this investigation, contemporary FDA-approved therapies for STS are associated with increased risk of AEs Full article