STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Март 14, 2024

Background Cervical cancer poses a significant global threat to women’s health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of disease. Given immunosuppressive microenvironment cervical cancer, it is imperative explore novel perspectives. In this regard, STING agonists have emerged promising candidates. Methods The expression profiles clinicopathological data were obtained from Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) datasets. Prognostic analysis downstream genes (CCL5, CXCL9, CXCL10) infiltration conducted using Kaplan-Meier Plotter, ESTIMATE, deconvo_CIBERSOR . Single-cell RNA-seq (scRNA-seq) was evaluate potential MSA-2 treatment employing SingleR, chi-squared test, Set Enrichment Analysis (GSEA). Cellular interaction utilized CellChat package assess potentiation cellular following administration. Murine tumor models involving U14 TC-1, conducted, IF tissue subsequently status after treatment. Results Prognosis correlated with elevated genes, indicating prolonged survival reduced recurrence. These positively infiltration, influencing stromal scores, estimate scores. Specific cell populations, including CD8 + T cells, M1-type macrophages, NK follicular helper associated genes. scRNA-seq classic immune-excluded model revealed that exerts priming activating functions on vital components within TME, intensifies their intercellular communications. vivo assay ultimately demonstrated MSA-2, either standalone or combination anti-PD-1, effectively suppressed growth subcutaneous tumors. Moreover, strategy significantly augmented efficacy compared anti-PD-1 monotherapy by eliciting robust antitumor response. Conclusion This study highlights pivotal role pathway reshaping cancer. Combining inhibitors presents transformative approach, holding promise for improved prognosis. Further investigations are warranted broader landscape long-term effects

Язык: Английский

---

Society for Immunotherapy of Cancer (SITC) consensus statement on essential biomarkers for immunotherapy clinical protocols

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(3), С. e010928 - e010928

Опубликована: Март 1, 2025

Immunotherapy of cancer is now an essential pillar treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration new strategies incorporating agents in clinical practice. Immunotherapies perturb complex system interactions among genomically unstable cells, diverse cells within the microenvironment including systemic adaptive innate cells. The drive to develop increasingly effective immunotherapy regimens tempered by risk immune-related adverse events. Evidence-based biomarkers that measure potential therapeutic response and/or toxicity critical guide optimal patient care contextualize results trials. Responding lack guidance on biomarker testing early-phase trials, we propose definition listing recommended inclusion all such protocols. These recommendations based consensus provided Society Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty input from SITC Pathology Biomarker Committees Journal ImmunoTherapy readership. A consensus-based selection was conducted using Delphi survey SCION faculty. Regular updates these planned. inaugural list includes complete blood count differential generate neutrophil-to-lymphocyte ratio or immune-inflammation index, serum lactate dehydrogenase albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, mutational burden. Inclusion across trials will capture variation provide deeper insight into novel established therapies, support improved stratification later-phase

Язык: Английский

---

Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?

Neuro-Oncology, Год журнала: 2023, Номер 26(2), С. 211 - 225

Опубликована: Ноя. 23, 2023

Abstract Glioblastoma (GBM)’s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, uncertain. Trial failures result from multiple factors, ranging intrinsic tumor biology to trial design. Understanding and basic science of these 6 compelled other immunotherapies reaching point advanced testing. We need understand more in human GBMs early trials: “window opportunity” design may be best complex changes brought about immunotherapeutic perturbations GBM microenvironment. The convergence increased safety image-guided biopsies with “multi-omics” small cell numbers now permits longitudinal sampling biofluids dissect temporal microenvironment as a function immunotherapy.

Язык: Английский

---

Spatial single-cell profiling and neighbourhood analysis reveal the determinants of immune architecture connected to checkpoint inhibitor therapy outcome in hepatocellular carcinoma

Gut, Год журнала: 2024, Номер unknown, С. gutjnl - 332837

Опубликована: Сен. 30, 2024

Background The determinants of the response to checkpoint immunotherapy in hepatocellular carcinoma (HCC) remain poorly understood. organisation immune tumour microenvironment (TME) is expected govern outcomes but spatial immunotypes defined. Objective We hypothesised that deconvolution network architectures could identify clinically relevant HCC. Design conducted highly multiplexed imaging mass cytometry on HCC tissues from 101 patients. performed in-depth single-cell analysis a discovery and validation cohort deconvolute heterogeneity architecture develop classification was tested for prediction inhibitor (ICI) therapy. Results Bioinformatic identified 23 major immune, stroma, parenchymal cell types TME. Unsupervised neighbourhood detection based interaction cells three with differing involvement checkpoints dominated by either CD8 T-cells, myeloid or B- CD4 T-cells. used these define reflect higher level intratumour organisation: depleted, compartmentalised enriched. Progression-free survival under ICI therapy differed significantly between improved enriched In patients heterogeneity, presence one area governed long-term survival.

Язык: Английский

---

Versican Associates with Tumor Immune Phenotype and Limits T-cell Trafficking via Chondroitin Sulfate

Cancer Research Communications, Год журнала: 2024, Номер 4(4), С. 970 - 985

Опубликована: Март 22, 2024

Abstract Immunotherapies for cancers of epithelial origin have limited efficacy, and a growing body evidence links the composition extracellular matrix (ECM) with likelihood favorable response to treatment. The ECM may be considered an immunologic barrier, restricting localization cytotoxic immune cells stromal areas inhibiting their contact tumor cells. Identifying components this barrier could provide targets that whether degraded in situ support antitumor immunity improve immunotherapy response. Using library primary triple-negative breast cancer tissues, we correlated CD8+ T-cell identified proteoglycan, versican (VCAN), as putative member barrier. Our analysis reveals associates location VCAN expression, specific glycovariant [defined through pattern posttranslational attachments glycosaminoglycans (GAG)], cell types produce variant. In functional studies, isomers chondroitin sulfate presented on opposing roles being either supportive or trafficking, removal GAGs ameliorates these effects trafficking. Overall, conclude can inhibit trafficking within microenvironment depending present, is major component defines type immunotherapy. Significance: has been poor toward solid tumors despite infiltrating into tumor. associated impacting infiltration article its structural modification, having key role invasion.

Язык: Английский

---

Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity

Science Immunology, Год журнала: 2024, Номер 9(94)

Опубликована: Апрель 26, 2024

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional cell-recruiting chemokine system, suggesting existence cell exclusion mechanisms that impair infiltration. Using genome-wide vitro screening platform, we identified role for phospholipase A2 group 10 (PLA2G10) protein exclusion. PLA2G10 up-regulation is widespread cancers associated with poor infiltration tumor tissues. overexpression immunogenic mouse tumors excluded infiltration, resulting resistance to anti-PD-1 immunotherapy. can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated mobility. Ablation PLA2G10's enzymatic activity enhanced sensitized PLA2G10-overexpressing immunotherapies. Our study implicates suggests potential target

Язык: Английский

---

Progressive T cell exhaustion and predominance of aging tissue associated macrophages with advancing disease stage in penile squamous cell carcinoma

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 5, 2025

Язык: Английский

---

Exploiting the CXCR3/CXCL10 pathway to override tumor immune suppression by enhancing immune trafficking and effector cell priming in head and neck squamous cell carcinoma

Опубликована: Апрель 28, 2025

ABSTRACT The immune-suppressive nature of the tumor microenvironment (TME) has limited impact immune checkpoint blockade in many cancers, often by restricting infiltration and activation anti-tumoral CD8+ T, CD4+ NK cells. Here, we utilized murine models head neck squamous cell carcinoma demonstrated that intratumoral (IT) delivery CXCL10 drives elimination inhibits recurrence. T cells recruited to tumors display enhanced activation, increased antigen specificity, decreased markers exhaustion, indicating not only directs migration, but also enhances effector functions. Despite into tumors, show presence proliferation tumor-draining lymph nodes (TdLNs), consistent with presentation trafficking these between TdLNs. stunts angiogenesis lymphangiogenesis within TME, which likely contributes its antitumoral effects. Finally, clearance was observed combining IT anti-PD-1. Together, findings provide rationale for clinical evaluation as a strategy enhance efficacy immunotherapy. Graphical Abstract SUMMARY suppresses growth promotes memory recruiting microenvironment, promoting tumor-specific recognition functions, slowing inhibiting angiogenesis. directly indirectly mobilizes an network together supports microenvironment.

Язык: Английский

---

Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июль 3, 2023

This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation microenvironment (TME). We summarize previous research efforts leveraging these observations targeting processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents immunotherapy. However, their overall survival benefit over conventional therapy remains limited certain tumors exhibit poor response therapy. Additionally, whilst preclinical studies shown several components coagulome curb effective anti-tumor immune responses, clinical reporting combinations anticoagulants with immunotherapies demonstrated variable treatment By reviewing current state literature this topic, we address key questions future directions in field, answers which are crucial for developing strategies reprogram TME order further field cancer

Язык: Английский

---

Immune cell topography of head and neck cancer

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(7), С. e009550 - e009550

Опубликована: Июль 1, 2024

Background Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are options for recurrent/metastatic HNSCC; however, less than 20% patients respond. To increase this response rate, it is fundamental to our understanding the spatial tumor immune microenvironment (TIME). Methods In total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified cells, CD163+macrophages, B CD8+T CD4+T helper cells regulatory T (Tregs) in treatment-naive surgical resection (n=29) biopsies (n=18). further characterize tumor-infiltrating stained (n=12) five-color tumor-resident including CD103, Ki67, CD8 pan-cytokeratin. Secretome analysis was performed on matched suspensions (n=11) measure protein levels. Results Based infiltrates, four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, immune-desert. We found higher cytokine levels infiltrated tumors compared other immunotypes. While highest infiltrates observed invasive margin all CD163+macrophages Tregs had tendency infiltrate center. Within center, especially stayed at stroma, whereas followed by more often localized within fields. Also, away from formed aggregates while tended be closely located each other. Across various anatomical sites neck, oral cavity exhibited densities Tregs. Moreover, distance shortest carcinoma (OCSCC), suggesting interaction between lymphocytes cells. fraction 10 µm lowest OCSCC, indicating fewer myeloid/T-cell suppressive interactions OCSCC. Conclusions comprehensively described TIME using unique data set specimens. discovered that composition, as well relative localization TIME, differed distinct neck.

Язык: Английский

---