Cancer research communications最新文献

The tumor microenvironment of brain metastases has become a focus in the development of immunotherapeutic drugs. However, countless patients with brain metastasis have not experienced clinical benefit. Thus, understanding the immune cell composition within brain metastases and how immune cells interact with each other and other microenvironmental cell types may be critical for optimizing immunotherapy. We applied spatial whole-transcriptomic profiling with extensive multiregional sampling (19-30 regions per sample) and multiplex IHC on formalin-fixed, paraffin-embedded lung cancer brain metastasis samples. We performed deconvolution of gene expression data to infer the abundances of immune cell populations and inferred spatial relationships from the multiplex IHC data. We also described cytokine networks between immune and tumor cells and used a protein language model to predict drug-target interactions. Finally, we performed deconvolution of bulk RNA data to assess the prognostic significance of immune-metastatic tumor cellular networks. We show that immune cell infiltration has a negative prognostic role in lung cancer brain metastases. Our in-depth multiomics analyses further reveal recurring intratumoral immune heterogeneity and the segregation of myeloid and lymphoid cells into distinct compartments that may be influenced by distinct cytokine networks. By using computational modeling, we identify drugs that may target genes expressed in both tumor core and regions bordering immune infiltrates. Finally, we illustrate the potential negative prognostic role of our immune-metastatic tumor cell networks. Our findings advocate for a paradigm shift from focusing on individual genes or cell types toward targeting networks of immune and tumor cells.

Significance: Immune cell signatures are conserved across lung cancer brain metastases, and immune-metastatic tumor cell networks have a prognostic effect, implying that targeting cytokine networks between immune and metastatic tumor cells may generate more precise immunotherapeutic approaches.

Significance: Genomic features of LBCL that can be detected by clinical laboratory assays may predict for resistance to first-line immunochemotherapy, as well as support the exploration of genomic features as biomarkers of response to therapies which could be offered to patients who experience disease progression.

Superoxide dismutase (SOD) catalyzes the highly reactive superoxide anion to form hydrogen peroxide, which facilitates cell proliferation and death. We investigated whether red cell SOD (R-SOD) activity is associated with an increased risk of cancer in a Japanese general population. We prospectively analyzed data from 1,921 participants (800 men and 1,121 women; age, 58.7 ± 14.7 years) in a Hidaka cohort study. After a median follow-up period of 10.9 years, 160 participants had developed cancer. The Cox proportional hazards model was used to estimate quartile-specific HRs and 95% confidential intervals (CI) for cancer risk. After adjustment for potential cancer risk factors including age, sex, current smoking habit, alcohol use, physical activities, body mass index, plasma immunoreactive insulin, and non-high-density lipoprotein cholesterol levels, we found a significant association between R-SOD activity and an increased risk of cancer (HR, 1.61; 95% CI, 1.03-2.52; P = 0.037). In analyses conducted separately by sex, a significant association was found in men (HR, 2.49; 95% CI, 1.35-4.59; P = 0.003) but not women (HR, 1.46; 95% CI, 0.70-3.05; P = 0.320). After excluding participants who developed cancer within 5 years of the baseline survey, the association was more evident in men (HR, 4.64; 95% CI, 1.88-11.45; P = 0.001). We found no association with cancer risk in women (HR, 1.01; 95% CI, 0.39-2.65; P = 0.983). Increased R-SOD activities were associated with an increased risk of cancer, particularly in men in this population.

Significance: Our study is the first to show that increased R-SOD activity is associated with a significantly higher cancer risk in men but not in women. Antioxidative enzymes such as SOD are essential for maintaining cellular redox balance. Their roles in cancer development and prevention are yet to be fully elucidated.

The present study investigated the relationship between metabolic phenotypes and the risk of cancer in a Japanese population using the criteria of metabolic phenotypes based on an examination and those based on questionnaires. We used data from 25,357 subjects for examination-based analyses and those from 53,042 subjects for questionnaire-based analyses in the Japan Multi-Institutional Collaborative Cohort Study. Metabolic phenotypes were defined by classifying subjects according to their BMI (obesity: BMI ≥25 kg/m2; normal weight: BMI <25 kg/m2) and the number of metabolic abnormalities. Metabolic abnormalities were defined according to metabolic syndrome components of the Joint Interim Statement Criteria for examination-based analyses and self-reported histories of diabetes, dyslipidemia, and hypertension for questionnaire-based analyses. Cox proportional hazards regression analyses adjusted for potential confounders were performed for total and site-specific cancer incidence according to metabolic phenotypes. Metabolically unhealthy obesity (MUHO) was significantly associated with cancer incidence in both examination-based [HR (95% CI): 1.17 (1.01-1.36)] and questionnaire-based analyses [HR (95% CI): 1.15 (1.04-1.26)]. Regarding site-specific cancer in questionnaire-based analyses, metabolically healthy obesity and MUHO were associated with colorectum and liver cancers in all subjects and with breast cancer in female subjects. Subjects with a metabolically unhealthy normal weight had a higher risk of pancreatic cancer. Moreover, MUHO was associated with corpus uteri cancer in female subjects. This prospective cohort study suggests that metabolic phenotypes are important risk factors for total and some site-specific cancers in Japanese adults.

Background: Aberrant alternative splicing can generate neoantigens, which can themselves stimulate immune responses and surveillance. Previous methods for quantifying splicing-derived neoantigens are limited by independent references and potential batch effects.

Results: Here, we introduce SpliceMutr, a bioinformatics approach and pipeline for identifying splicing derived neoantigens from tumor and normal data. SpliceMutr facilitates the identification of tumor-specific antigenic splice variants, predicts MHC-binding affinity, and estimates splicing antigenicity scores per gene. By applying this tool to genomic data from The Cancer Genome Atlas (TCGA), we generate splicing-derived neoantigens and neoantigenicity scores per sample and across all cancer types and find numerous correlations between splicing antigenicity and well-established biomarkers of anti-tumor immunity. Notably, carriers of mutations within splicing machinery genes have higher splicing antigenicity, which provides support for our approach. Further analysis of splicing antigenicity in cohorts of melanoma patients treated with mono- or combined immune checkpoint inhibition suggests that the abundance of splicing antigens is reduced post-treatment from baseline in patients who progress. We also observe increased splicing antigenicity in responders to immunotherapy, which may relate to an increased capacity to mount an immune response to splicing-derived antigens.

Conclusions: We find the splicing antigenicity to be higher in tumor samples when compared to normal, that mutations in the splicing machinery result in increased splicing antigenicity in some cancers, and higher splicing antigenicity is associated with positive response to immune checkpoint inhibitor therapies. Further, this new computational pipeline provides novel analytical capabilities for splicing antigenicity and is openly available for further immuno-oncology analysis.

Elraglusib (9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK3) with pre-clinical studies demonstrating broad activity against many tumour types. Promising early-phase clinical trial data led to FDA orphan drug status, and a randomized phase 2 study in combination with cytotoxic chemotherapy in pancreatic cancer has recently completed its recruitment. Similarly, single-agent responses in adult T-cell leukaemia/lymphoma and melanoma, and combination treatment data in several other tumour types have been encouraging. The elraglusib mechanism of action is unknown, but it is unlikely to act through GSK3 inhibition because cytotoxicity is observed below the IC50 for GSK3 and other small molecule GSK3 inhibitors do not produce cytotoxic effects, at least in lymphoma cells. We show here that elraglusib perturbs chromosomal alignment to cause a mitotic arrest in multiple tumour lines. This arrest is caused by direct microtubule depolymerization, which prevents the attachment of kinetochores to microtubules. At clinically relevant doses, these mitotically arrested cells eventually undergo mitotic slippage, leading to gross chromosome missegregation, DNA damage and apoptosis. These effects explain the cytotoxicity of elraglusib because temporarily pausing cell cycle progression with the CDK4/6 inhibitor palbociclib abolishes any drug-induced genotoxicity and apoptosis. In summary, elraglusib acts as a direct microtubule destabilizer both in vitro and across multiple cancer types, resulting in mitotic arrest, DNA damage and apoptosis. These effects likely account for its broad pan-cancer activity, which does not rely upon GSK3 inhibition as they are not replicated by other GSK3 inhibitors.

Genomic testing, which analyzes tumor cells or circulating tumor DNA to guide cancer treatment, is increasingly used in precision oncology. However, data on racial and ethnic disparities in its use are limited. This retrospective cohort study included patients diagnosed with stage IV breast, colorectal, non-small cell lung, or prostate cancer in 2014-2019. Patients were identified from an institutional multilevel data warehouse and their data was linked to an institutional genomics database and electronic health records. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the receipt of tumor-specific genomic testing among non-Hispanic (NH) Black and NH White patients, stratified by cancer type. The linked dataset included 3,461 patients, 44.5% of whom received genomic testing. NH Black patients with prostate cancer were less likely to use genomic testing vs. NH White patients across the study period (fully adjusted OR: 0.55, 95% CI: 0.32, 0.95), as were NH Black patients diagnosed with breast cancer in 2014-2016 (OR adjusted for patient-level covariates: 0.34, 95% CI: 0.11, 0.99). No differences in testing were observed between NH Black and NH White patients with colorectal or non-small cell lung cancer, or breast cancer diagnosed in 2017-2019. Lower documented use of tumor-specific genomic testing among NH Black patients with prostate cancer across the study period underscores the need to monitor trends and address disparities in the use of emerging precision oncology technologies. Future work targeting multilevel barriers to genomic testing is a crucial next step forward.

Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers including castration-resistant prostate cancer (CRPC). Despite its efficacy, resistance to Olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PINK1 gene in conferring Olaparib resistance in CRPC cells. We investigated the transcriptomic and functional differences in mitochondrial activity between Olaparib-resistant (2B-OlapR, LN-OlapR) and treatment naïve prostate cancer (PCa) cells (C4-2B, LNCaP) in both castration sentitive and resistant settings. Through RNA sequencing and Gene Set Enrichment Analysis (GSEA), we identified significant enrichment of mitochondrial and oxidative phosphorylation-related gene sets in Olaparib Resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity compared to parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in Olaparib-resistant cells. Furthermore, overexpression of the PINK1 gene was observed in resistant cells, which was correlated with resistance to Olaparib and poor clinical outcomes in prostate cancer patients. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to Olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming Olaparib resistance in PCa.

Nectin-4 is a cell-adhesion molecule expressed at various levels in many solid tumors, including urothelial cancer. As means to reduce on-target skin toxicity observed with enfortumab vedotin, an anti-nectin-4-MMAE ADC approved for patients with advanced urothelial cancer, 15A7.5, an anti-nectin-4 monoclonal antibody that exhibited differential nectin-4 binding between tumor and primary keratinocytes, was selected for the development of ETx-22. Exatecan, a topoisomerase I inhibitor, was chosen as payload. ETx-22 ADC induced rapid and long-lasting tumor regression in various patient derived xenograft models expressing low to high levels of nectin-4 and also in MonoMethyl Auristatin-E resistant xenograft model. ETx-22 has a highest non severely toxic dose of over 20 mg/kg in non-human primates without signs of important skin toxicity. ETx-22 represents a valuable therapy, for the treatment of patients with nectin-4 expressing tumors including those that have become resistant to enfortumab vedotin treatment.

High-grade serous ovarian cancer remains a poorly understood disease with a high mortality rate. Although most patients respond to cytotoxic therapies, a majority will experience recurrence. This may be due to a minority of drug-resistant cancer stem-like cells (CSC) that survive chemotherapy and are capable of repopulating heterogeneous tumors. It remains unclear how CSCs are supported in the tumor microenvironment (TME) particularly during chemotherapy exposure. Tumor-associated macrophages (TAM) make up half of the immune population of the ovarian TME and are known to support CSCs and contribute to cancer progression. TAMs are plastic cells that alter their phenotype in response to environmental stimuli and thus may influence CSC maintenance during chemotherapy. Given the plasticity of TAMs, we studied the effects of carboplatin on macrophage phenotypes using both THP1- and peripheral blood mononuclear cell (PBMC)-derived macrophages and whether this supports CSCs and ovarian cancer progression following treatment. We found that carboplatin exposure induces an M1-like proinflammatory phenotype that promotes SOX2 expression, spheroid formation, and CD117+ ovarian CSCs, and that macrophage-secreted CCL2/MCP-1 is at least partially responsible for this effect. Depletion of TAMs during carboplatin exposure results in fewer CSCs and prolonged survival in a xenograft model of ovarian cancer. This study supports a role for platinum-based chemotherapies in promoting a transient proinflammatory M1-like TAM that enriches for CSCs during treatment. Improving our understanding of TME responses to cytotoxic drugs and identifying novel mechanisms of CSC maintenance will enable the development of better therapeutic strategies for high-grade serous ovarian cancer. Significance: We show that chemotherapy enhances proinflammatory macrophage phenotypes that correlate with ovarian cancer progression. Given that macrophages are the most prominent immune cell within these tumors, this work provides the foundation for future translational studies targeting specific macrophage populations during chemotherapy, a promising approach to prevent relapse in ovarian cancer.