British Journal of Cancer最新文献

Background: Dendritic cell (DC) vaccine is a promising immunotherapy for hepatocellular carcinoma (HCC) via triggering antigen-specific anti-tumor immunity. Hypoxia contributes to higher level and broader spectrum of antigen expression in tumor cells.

Methods: This study aims to compare immunological activity and therapeutic efficacy between hypoxic and normoxic HCC cell line lysate-pulsed DC vaccines.

Results: The results showed that hypoxic HCC cell line lysate-pulsed DC vaccines exhibited a stronger activity in producing interleukin-12 and promoting T cell proliferation and cytotoxicity in vitro. In HCC mice, hypoxic HCC cell line lysate-pulsed DC vaccines displayed a better efficacy in improving survival time and tumor volume and inducing intratumoral cytotoxic T cell infiltration and activation as well as tumor cell apoptosis. Adenylate kinase 4-derived antigens were important for hypoxic HCC cell line lysate-pulsed DC vaccine-elicited T cell killing.

Conclusions: In conclusion, this study demonstrated hypoxic HCC cell line lysate-pulsed DC vaccine as a potential therapeutic strategy for HCC.

Background: Hepatic metastases of GIST might be the dominant site of progression and resistant to available tyrosine kinase inhibitors (TKIs). Selective internal radiation therapy (SIRT) offers treatment by intratumoral radiation up to 200 Gy. We analyzed the hepatic progression-free survival (H-PFS) in a consecutive patient cohort.

Methods: Twenty-six patients (median age 57.6 years) with biopsy proven liver metastases of GIST were treated by SIRT. All had RECIST documented tumor progression, and 24/26 patients had up to four lines of pretreatment. Mutational status was 'quadruple wildtype' (q-wt, n = 5), KIT exon 11/9/13 in n = 15/4/1 cases and PDGFRα (n = 1). Median follow-up of this retrospective analysis of a prospectively kept database is 33.6 months.

Results: Median H-PFS was 16 months (range, 4-54+ months, 95% CI 6.5-25.4 months) and OS after SIRT was 28 months (95% CI 17.2-28.7 months). Best H-PFS was observed in patients with 'q-wt' at 25 months (range, 6+-54 months, 95% CI 16.2-33.8 months). The worst outcome was for KIT exon 11 mutations plus secondary mutations with 7 months (range, 4-33 months, 95% CI, 4.2-9.8 months).

Conclusions: 90Y-SIRT is a potent treatment for patients with liver metastases of GIST resistant to TKI therapy. In patients with 'q-wt' GIST, SIRT is an option for first-line use.

Background: PI3K pathway activation is a common and early event in prostate cancer, from loss of function mutations in PTEN, or activating mutations in PIK3Ca or AKT leading to constitutive activation, induction of growth factor-receptors kinase EphB4 and its ligand ephrin-B2. We hypothesized that induction of EphB4 is an early event required for tumor initiation. Secondly, we hypothesized that EphB4 remains relevant when prostate cancer becomes androgen independent.

Methods: Genetic mouse model of conditional PTEN deletion in prostate epithelium induces tumor in all mice. We tested this model against EPHB4 wild type and deleted in prostate epithelium. This allowed us to test its role in tumor initiation. We also tested an orthogonal approach by using decoy soluble EphB4 to block bidirectional signaling resulting from EphB4-ephrin-B2 interaction. Role of EphB4-ephrin-B2 in androgen deprived mice was tested for role in refractory cancer model.

Results: PTEN deletion induces EphB4 and ephrin-B2 in prostate cancer which was substantially reduced when EPHB4 is deleted in the same prostate epithelial cells. sEphB4-alb fusion protein with improved pharmacokinetics similarly inhibited tumor formation, thus establishing the role in tumor initiation. sEphB4-alb retained the efficacy in castration resistant androgen independent prostate cancer. We have thus observed that induction of EphB4 is required for the initiation of prostate cancer in PTEN null mouse and that signaling downstream from EphB4 is required in androgen deprivation and thus castration resistant prostate cancer. Pharmacological inhibition of EphB4 pathway reproduced the results. Targeting EphB4 should be tested in prostate cancer especially those resistant to androgen deprivation therapy.

Conclusions: EphB4 and ephrin-B2 receptor ligand pair is induced in PTEN null prostate cancer, which significantly contributes to the tumor initiation. Secondly, EphB4-ephrin-B2 pathway continue to promote tumor progression even in androgen deprivation and thus hormone refractory tumor. EphB4-ephrin-B2 may be candidates for precision medicine with biomarker-based patient selection with and without concurrent standard of care.

Background: Understanding the proteomic-level heterogeneity of the tumor microenvironment (TME) in colorectal cancer (CRC) is crucial due to its well-known heterogeneity. While heterogenous CRC has been extensively characterized at the molecular subtype level, research into the functional heterogeneity of fibroblasts, particularly their relationship with extracellular matrix (ECM) alterations, remains limited. Addressing this gap is essential for a comprehensive understanding of CRC progression and the development of targeted therapies.

Methods: 24 tissue samples from 21 CRC patients, along with adjacent normal tissues (NAT), were collected and decellularized using a detergent-based method to enrich the ECM component. Proteomic analysis of ECM-enriched samples was performed using tandem mass tag (TMT) spectrometry, followed by statistical analysis including differential expression protein (DEP) analysis. Single-cell RNA sequencing (scRNA-Seq) data from public datasets were integrated and analyzed to delineate cell states within the TME. Bulk tissue RNA-Seq and bioinformatics analysis, including consensus molecular subtype (CMS) classification and single-cell level deconvolution of TCGA bulk RNA-seq data, were conducted to further explore gene expression patterns and TME composition.

Results: Differential cellular origin of the NAT and tumorous ECM proteins were identified, revealing 110 ECM proteins enriched in NAT and 28 ECM proteins in tumor tissues. Desmoplastic and WNT5A⁺ inflammatory fibroblasts were indicated as the sources of tumor-enriched ECM proteins, while ADAMDEC1⁺ expressing fibroblasts and PI16⁺ expressing fibroblast were identified as the sources of NAT-enriched ECM proteins. Deconvolution of bulk RNA-seq of CRC tissues discriminated CMS-specific fibroblast state, reflecting the biological traits of each CMS subtype. Specially, seven ECM genes specific to mesenchymal subtype (CMS4), including PI16⁺ fibroblast-related 4 genes (SFRP2, PRELP, OGN, SRPX) and desmoplastic fibroblast-related 3 genes (THBS2, CTHRC1, BGN), showed a significant association with poorer survival in patient with CRC.

Conclusion: We conducted an extracellular matrix (ECM)-focused profiling of the TME by integrating quantitative proteomics with single-cell RNA sequencing (scRNA-seq) data from CRC patients. We identified the ECM proteins of NAT and tumor tissue, and established a cell-matrisome database. We defined mesenchymal subtype-specific molecules associated with specific fibroblast subtypes showing a significant association with poorer survival in patients with CRC. Our ECM-focused profiling of tumor stroma provides new insights as indicators for biological processes and clinical endpoints.

Background: Existing prognostic models for breast cancer (BC) brain metastases (BM) overlook neurological symptoms. Thus, we explored the incidence and prognostic relevance of neurological symptoms in a real-world cohort of BC patients with BM.

Methods: The Vienna Brain Metastasis Registry identified BC patients with BM between 1992 and 2020, categorised by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), HER2 overexpressing (HER2+), and triple-negative (TN).

Results: A total of 716 patients with BM from BC were included. In total, 80% (573/716) of the patients presented with neurological symptoms at BM diagnosis. Across all BC subtypes, asymptomatic patients presented with a significantly longer median OS from diagnosis of BM compared to symptomatic patients (p < 0.05; log-rank test; HR+ BC 29 vs. 9 months; HER2+ BC 24 vs. 12 months; TN 12 vs. 6 months). In multivariate analysis with the BC-specific Graded Prognostic Assessment (Breast-GPA: HR:1.4; 95% CI:1.3-1.5; p < 0.001), the presence of neurological symptoms at diagnosis (HR:1.6; 95% CI: 1.4-1.9; p < 0.001) presented as independently associated with OS from time of BM diagnosis, respectively.

Conclusions: Neurological burden at BM diagnosis independently predicts survival in BC patients. Our findings emphasise incorporating the symptom status in the prognostic evaluation and reassessing BM screening in high-risk patients during prospective clinical trials.

Background: Cells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death in these contexts and determined the mechanisms responsible.

Methods: We used cervical, breast, lung and ovarian cancer cells bearing mutations in BRCA1 or ATM and depleted SETD1A using siRNA or CRISPR/Cas9. We assessed the effects of the PARPi Olaparib on cell viability, homologous recombination, and DNA repair. We assessed underlying transcriptional perturbations using RNAseq. We used The Cancer Genomics Atlas (TCGA) and DepMap to investigate patient survival and cancer cell characteristics.

Results: Loss of SETD1A from both BRCA1-deficient and ATM-deficient cancer cells was associated with resistance to Olaparib, explained by partial restoration of homologous recombination. Mechanistically, SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with sensitivity to Olaparib in these cells. Accordingly, when SETD1A or EME1 was lost, BRCA1 or ATM-mutated cells became resistant to Olaparib, and homologous recombination was partially restored.

Conclusions: Loss of SETD1A or EME1 drives cellular resistance to Olaparib in certain genetic contexts and may help explain why patients develop resistance to PARP inhibitors in the clinic.

Background: Tumor acidosis causes resistance to immune checkpoint blockade (ICB). We hypothesized that a "pH-sensitizer" can increase tumor extracellular pH (pHe) and improve tumor control following ICB. We also hypothesized that pHe measured with acidoCEST MRI can predict improved tumor control with ICB.

Methods: We tested the effects of pH-sensitizers on proton efflux rate (PER), cytotoxicity, T cell activation, tumor immunogenicity, tumor growth and survival using 4T1 and B16-F10 tumor cells. We measured in vivo tumor pHe of 4T1 and B16-F10 models with acidoCEST MRI.

Results: Among the pH-sensitizers tested, someprazole caused the greatest reduction in PER without exhibiting cytotoxicity or reducing T cell activation. Esomeprazole improved 4T1 tumor control with ICB administered one day after the pH-sensitizer. Tumor pHe positively correlated with TCF-1 + CD4 effector and CD8 T cell intratumoral frequencies and predicted improved 4T1 tumor control with ICB. For comparison, esomeprazole had a mild effect on B16-F10 tumor pHe, and worsened tumor control with ICB and increased intratumoral myeloid and dendritic cell (DC) frequencies.

Conclusions: A pH-sensitizer can improve tumor control with ICB, and acidoCEST MRI can be used to measure pHe and predict tumor control, but only in the 4T1 model and not the B16-F10 model.

Acute lymphoblastic leukaemia (ALL) is a rare and heterogeneous disease. The ALLTogether consortium has implemented a treatment protocol to improve outcome and reduce treatment-related toxicity across much of Europe. The consortium provides the opportunity to design translational research on patient material stored in national biobanks. However, there are currently no standardized guidelines for the types of material, processing, and storage for leukaemia biobanking. To address this gap, we conducted a modified Delphi survey among 53 experts in different roles related to leukaemia. The first round consisted of 63 statements asking for level of agreement. The second round refined some to reach consensus, using yes-no and multiple-option answers. Key recommendations include cryopreservation of cells from diagnosis, post-induction, post-consolidation, and relapse, with at least two aliquots of plasma and serum, and cerebrospinal fluid from diagnosis, day15, and post-induction. It was advised to distribute cells across multiple vials for various research projects, and to collect data on sample processing, cell viability, and blast percentage. Quality monitoring and user feedback were strongly recommended. The Delphi survey resulted in strong recommendations that can be used by national biobanks to harmonize storage of samples from patients with ALL and ensure high-quality cryopreserved cells for research studies.

Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) primarily polarize into the M2-phenotype. Our previous study showed that the small GTPase Rab37 mediates IL-6 trafficking in macrophages for M2 polarization. Here, we uncover an unconventional role of Rab37, independent of vesicle trafficking, in promoting M2 polarization of TAMs.

Methods: The gene profiles in wild-type and Rab37 knockout (KO) bone marrow-derived macrophages (BMDMs) were analyzed using cDNA microarray. The mechanism of Rab37 in regulating the interferon (IFN) pathway was confirmed through in vitro/vivo assays and clinical studies.

Results: Type I IFN signaling was highly enriched in BMDMs from Rab37 KO mice. Moreover, Rab37 induction and decreased type I IFN genes were observed in macrophages treated with lung cancer-conditioned medium and epigenetic drugs, indicating an epigenetic regulation of Rab37 in TAMs. Mechanistically, GDP-bound Rab37 interacted with the nuclear localization sequence of STAT1 to sequest it in the cytosol from its transcription activities, thus leading to the downregulation of IFN genes. Clinically, CD163⁺/Rab37⁺/STAT1^cytosol in TAMs expression signature correlated with advanced tumor stages and poor survival of lung cancer patients.

Conclusions: Our findings highlight the cytosolic interaction of Rab37-STAT1 in M2 TAM polarization, with CD163⁺/Rab37⁺/STAT1^cytosol TAMs as a lung cancer prognosis biomarker.