Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer (NECTAR): a multi-center phase 2 study

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 11, 2024

Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer (LARC) patients with microsatellite stable (MSS) / mismatch repair-proficient (pMMR) tumors is an attractive, but debatable strategy. This phase 2, multicenter, prospective, single-arm study enrolled from 6 centers June 2021 to November 2022. Locally (LARC, cT

Язык: Английский

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Histopathological Aspects of the Prognostic Factors for Salivary Gland Cancers

Cancers, Год журнала: 2023, Номер 15(4), С. 1236 - 1236

Опубликована: Фев. 15, 2023

Salivary gland cancers (SGCs) are diagnosed using histopathological examination, which significantly contributes to their progression, including lymph node/distant metastasis or local recurrence. In the current World Health Organization (WHO) Classification of Head and Neck Tumors: Glands (5th edition), malignant benign epithelial tumors classified into 21 15 tumor types, respectively. All have potential for particular, mucoepidermoid carcinoma (MEC), adenoid cystic (AdCC), salivary duct carcinoma, not otherwise specified (NOS, formerly known as adenocarcinoma, NOS), myoepithelial epithelial–myoepithelial ex pleomorphic adenoma (PA) relatively prevalent. High-grade transformation is an important aspect progression in SGCs. MEC, AdCC, NOS a distinct grading system; however, universal histological system SGCs has yet been recommended. Conversely, PA considered benign; nonetheless, it should be cautiously treated avoid development metastasizing/recurrent PA. The aim this review describe aspects prognostic factors discuss genes molecules used diagnostic tools that might treatment target future.

Язык: Английский

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WTAP‐induced N⁶‐methyladenosine of PD‐L1 blocked T‐cell‐mediated antitumor activity under hypoxia in colorectal cancer

Cancer Science, Год журнала: 2024, Номер 115(6), С. 1749 - 1762

Опубликована: Март 20, 2024

Abstract N 6 ‐Methyladenosine (m A) is a important process regulating gene expression post‐transcriptionally. Programmed death ligand 1 (PD‐L1) major immune inhibitive checkpoint that facilitates evasion and expressed in tumor cells. In this research we discovered Wilms' 1‐associated protein (WTAP) degradation caused by ubiquitin‐mediated cleavage cancer cells (colorectal cancer, CRC) under hypoxia was inhibited Pumilio homolog (PUM1) directly bound to WTAP. WTAP enhanced PD‐L1 way m A‐dependent. A “reader,” Insulin‐like growth factor 2 mRNA‐binding (IGF2BP2) identified methylated transcripts subsequently fixed its mRNA. Additionally, found T‐cell proliferation cell‐killing effects were prevented overexpression of vitro vivo. Overexpression T from proliferating killing CRC maintaining the PD‐L1. Further evidence supporting WTAP–PD‐L1 regulatory axis human organoid tissues. Tumors with high levels appeared more responsive anti‐PD1 immunotherapy, when analyzing samples patients undergoing treatment. Overall, our findings demonstrated novel mechanism WTAP‐induced mRNA epigenetic regulation possible application targeting as immunotherapy for hypoxia.

Язык: Английский

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Saffron improves the efficacy of immunotherapy for colorectal cancer through the IL-17 signaling pathway

Journal of Ethnopharmacology, Год журнала: 2024, Номер 337, С. 118854 - 118854

Опубликована: Сен. 24, 2024

Язык: Английский

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PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 15, 2025

Programmed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of checkpoint inhibitor (ICI) therapy in various types cancer. Platelets are important components tumour microenvironment (TME) and widely involved development many cancer including colorectal (CRC). However, role PD-L1 positive platelets ICI for CRC remains unknown. We hypothesized that trigger sustain immunosuppression. The functional depletion effects TME were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1flox/flox) mouse models a subcutaneous model treated aspirin mAb established C57BL/6 N mice. found poor prognosis, CD8 + T exhaustion serve as novel noninvasive biomarker predicting immunotherapy patients CRC. transfer from to depends direct contact fibronectin-1/GPIbα/integrin α5β1 pathway. turn, can also induce cells. Animal experiments revealed antiplatelet pharmacological agents genetic potentiated antitumour effect treatment dependent manner. Our data suggest suppress immunity. Clinical combination ICIs may be an effective therapeutic strategy treating

Язык: Английский

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N6-methyladenosine RNA modification in PD-1/PD-L1: Novel implications for immunotherapy

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1878(3), С. 188873 - 188873

Опубликована: Фев. 25, 2023

Язык: Английский

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Biological function, regulatory mechanism, and clinical application of mannose in cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1878(6), С. 188970 - 188970

Опубликована: Авг. 30, 2023

Язык: Английский

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Interim result of phase II, prospective, single-arm trial of long-course chemoradiotherapy combined with concurrent tislelizumab in locally advanced rectal cancer

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Фев. 2, 2023

Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer, with modest benefits on tumor regression and survival. Since combined immune checkpoint inhibitors has been reported to have synergic effects. This study aims explore safety efficacy of long-course concurrent tislelizumab as a neoadjuvant regimen patients cancer. manuscript interim result prospective, multicenter, single-arm, phase II trial. Patients mid-to-low cancer clinical stages cT3-4a N0M0 or cT1-4a N1-2M0 were included. The received radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) three 21-day cycles capecitabine (1000 mg/m2, bid, day1-14) plus (200 mg, day8), followed by radical surgery 6-8 weeks after radiotherapy. primary endpoint was pathological complete response rate. (Clinical trial number: NCT04911517). A total 26 completed protocol between April 2021 June 2022. All chemoradiotherapy, 24 tislelizumab, two cycles. remission (ypT0N0) achieved in 50% (13/26) all proficient mismatch repair tumors. immune-related adverse event occurred 19.2% (5/26) patients. no CEA elevation age less than 50 more likely benefit from this regimen. Long-course low had favorable efficacy, does not increase complication rate surgery. Further needed confirm these results.

Язык: Английский

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ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Фев. 11, 2024

Abstract ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between mutations, molecular features, clinical outcomes melanoma patients. Cutaneous samples (n = 1577) were analyzed by next-generation sequencing. Samples stratified pathogenic/likely pathogenic mutation ( ARID1A/2/1B/5B ). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor burden (TMB)-high defined as 10 mutations/Mb. Transcriptomic signatures predictive response to immune checkpoint inhibitors—interferon gamma T-cell inflamed score calculated. Real-world overall survival (OS) information obtained from insurance claims data, with Kaplan–Meier estimates calculated time tissue collection until last date contact. Mann–Whitney U, Chi-square, Fisher exact tests applied where appropriate, p values adjusted for multiple comparisons. ARID2 mutations more prevalent cutaneous compared ARID1A (11.0%: n 451 vs 2.8%: 113), concurrent / 1.1% 46) samples. associated a high prevalence RAS pathway mutations— NF1 , 52.6%; 48.5%; ARID1A/2 63.6%; ARID-WT, 13.3%; < 0.0001) KRAS 3.5%; 3.1%; 6.5%; 1.0%; 0.018)), although BRAF less common ARID-mutated cohorts 31.9%; 35.6%; 26.1%; 50.4%; 0.0001). TMB-high 80.9%; 89.9%; 100%; 49.4%; 0.0001), while positivity similar across subgroups 43.8%; 51.1%; 52.5%; 44.9%; 0.109). Patients had higher dMMR/MSI-H those ARID-WT (2.7% 0.2%, 0.030). Median IFN-γ -mutated (IFN-γ: − 0.15 0.21, 0.0066; T-cell: 23.5 18.5, 0.041). ARID2- patients improved ARID-WT; (HR: 1.22 (95% CI 1.0–1.5), 0.022). No additional OS benefit observed anti-PD-1 therapy -WT. Melanoma exhibited markers ICI response, including TMB-H, immune-related signatures. Our data also suggests outcome irrespective anti-PD1 therapy.

Язык: Английский

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Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer

Cancer Immunology Immunotherapy, Год журнала: 2023, Номер 72(10), С. 3135 - 3147

Опубликована: Авг. 1, 2023

Abstract Background Immune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, role of ICI patients early-stage, operable CRC remains unclear. The aim this study was to investigate trials on neoadjuvant CRC. Materials and methods Scoping review clinical trial registries (Clinicaltrials.gov EU registers) PubMed/Medline database done up December 2022. Results Some 40 investigating were identified, including five published three conference abstracts. Preclinical phase I/II predominated only III trials. Few investigated as intervention (monotherapy). Trials rectal designed combined chemo(radio)therapy, 8 stating an MSI/dMMR status inclusion, one MSS/pMMR and, rest agnostic MMR status. Thirty-eight (95%) programmed cell death protein 1 (PD-1) or ligand (PD-L1) inhibitors. PD-1/PD-L1 vascular endothelial growth factor (VEGF) inhibitor cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, two each, respectively. Pathological complete primary outcome after surgery most frequently used endpoint. In cancer, six included a “watch wait” strategy response. No design colon identified. Conclusion High rates from early-stage are studies. Contemporary designs heterogeneous, few comparable inclusion criteria, use several drug combinations durations wide variation endpoints reported. Harmonizing translational aspects survival data is needed improved future impact.

Язык: Английский

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