Cancer Innovation最新文献

{"title":"A lactate-responsive gene signature predicts the prognosis and immunotherapeutic response of patients with triple-negative breast cancer","authors":"Kaixiang Feng,&nbsp;Youcheng Shao,&nbsp;Jun Li,&nbsp;Xiaoqing Guan,&nbsp;Qin Liu,&nbsp;Meishun Hu,&nbsp;Mengfei Chu,&nbsp;Hui Li,&nbsp;Fangfang Chen,&nbsp;Zongbi Yi,&nbsp;Jingwei Zhang","doi":"10.1002/cai2.124","DOIUrl":"https://doi.org/10.1002/cai2.124","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether a subset of lactate-responsive genes (LRGs) could be used to classify TNBC subtypes and predict patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Lactate levels were initially measured in different breast cancer (BC) cell types. Subsequently, MDA-MB-231 cells treated with 2-Deoxy-<span>d</span>-glucose or <span>l</span>-lactate were subjected to RNA sequencing (RNA-seq). The gene set variation analysis algorithm was utilized to calculate the lactate-responsive score, conduct a differential analysis, and establish an association with the extent of immune infiltration. Consensus clustering was then employed to classify TNBC patients. Tumor immune dysfunction and exclusion, cibersort, single-sample gene set enrichment analysis, and EPIC, were used to compare the tumor-infiltrating immune cells between TNBC subtypes and predict the response to immunotherapy. Furthermore, a prognostic model was developed by combining 98 machine learning algorithms, to assess the predictive significance of the LRG signature. The predictive value of immune infiltration and the immunotherapy response was also assessed. Finally, the association between lactate and various anticancer drugs was examined based on expression profile similarity principles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the lactate levels of TNBC cells were significantly higher than those of other BC cell lines. Through RNA-seq, we identified 14 differentially expressed LRGs in TNBC cells under varying lactate levels. Notably, this LRG signature was associated with interleukin-17 signaling pathway dysregulation, suggesting a link between lactate metabolism and immune impairment. Furthermore, the LRG signature was used to categorize TNBC into two distinct subtypes, whereby Subtype A was characterized by immunosuppression, whereas Subtype B was characterized by immune activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identified an LRG signature in TNBC, which could be used to predict the prognosis of patients with TNBC and gauge their response to immunotherapy. Our findings may help guide the precision treatment of patients with TNBC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of collagen subtypes of gastric cancer for distinguishing patient prognosis and therapeutic response","authors":"Di Wang,&nbsp;Jing Zhang,&nbsp;Jianchao Wang,&nbsp;Zhonglin Cai,&nbsp;Shanfeng Jin,&nbsp;Gang Chen","doi":"10.1002/cai2.125","DOIUrl":"https://doi.org/10.1002/cai2.125","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to collagen gene expression to indicate their prognosis and treatment response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA-STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform-independent collagen-subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified two subtypes of gastric adenocarcinoma: a high-expression collagen subtype (CS-H) and a low-expression collagen subtype (CS-L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS-L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3-kinase (PI3K)/Akt pathways were transcriptionally active in the CS-H subtype, while DNA repair activity was significantly greater in the CS-L subtype. <i>PIK3CA</i> was frequently amplified in the CS-H subtype, while <i>PIK3C2A</i>, <i>PIK3C2G</i>, and <i>PIK3R1</i> were frequently deleted in the CS-L subtype. CS-H subtype tumors were more sensitive to fluorouracil, while CS-L subtype tumors were more sensitive to immune checkpoint blockade. CS-L subtype was predicted to be more sensitive to HER2-targeted drugs, and CS-H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway-targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transc","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140949137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic effect of additional anlotinib and immunotherapy as second-line or later-line treatment in pancreatic cancer: A retrospective cohort study","authors":"Boyu Qin,&nbsp;Qi Xiong,&nbsp;Lingli Xin,&nbsp;Ke Li,&nbsp;Weiwei Shi,&nbsp;Qi Song,&nbsp;Qiong Sun,&nbsp;Jiakang Shao,&nbsp;Jing Zhang,&nbsp;Xiao Zhao,&nbsp;Jinyu Liu,&nbsp;Jinliang Wang,&nbsp;Bo Yang","doi":"10.1002/cai2.123","DOIUrl":"https://doi.org/10.1002/cai2.123","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of a second-line or later-line treatment strategy. We aimed to analyze the efficacy and safety of additional anlotinib, specifically anlotinib in combination with immunotherapy, in patients with PDAC who have failed first-line therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with pathological diagnosis of PDAC were additionally treated with anlotinib, and some patients were treated with anti-PD-1 agents at the same time, which could be retrospectively analyzed. The efficacy and safety of additional anlotinib were evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 23 patients were included. In patients treated with additional anlotinib, the overall median progression-free survival (PFS) was 1.8 months and the median overall survival (OS) was 6.3 months, regardless of anti-PD-1 agents. Among patients receiving additional anlotinib in combination with anti-PD-1 agents, median PFS and OS were 1.8 and 6.5 months, respectively. Adverse events (AEs) were observed in 16 patients (69.6%). In patients treated with additional anlotinib, the majority of AEs were grade 1–3. Univariate analysis revealed that patients with baseline red blood cell distribution width (RDW) &lt;14% treated with additional anlotinib plus anti-PD-1 agents had significantly longer OS than patients with baseline RDW ≥14% (<i>p</i> = 0.025). Patients with additional anlotinib plus anti-PD-1 agents as second-line therapy had a longer OS than those treated as later-line therapy (<i>p</i> = 0.012). Multivariate analysis showed that baseline RDW was the only independent risk factor for OS (<i>p</i> = 0.042).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The combination of anlotinib and immunotherapy represents an effective add-on therapy with tolerable AEs as second- or later-line therapy in patients with PDAC, particularly in patients with baseline RDW &lt;14%.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel progressive deep learning algorithm for uncovering multiple single nucleotide polymorphism interactions to predict paclitaxel clearance in patients with nonsmall cell lung cancer","authors":"Wei Chen,&nbsp;Haiyan Zhou,&nbsp;Mingyu Zhang,&nbsp;Yafei Shi,&nbsp;Taifeng Li,&nbsp;Di Qian,&nbsp;Jun Yang,&nbsp;Feng Yu,&nbsp;Guohui Li","doi":"10.1002/cai2.110","DOIUrl":"https://doi.org/10.1002/cai2.110","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The rate at which the anticancer drug paclitaxel is cleared from the body markedly impacts its dosage and chemotherapy effectiveness. Importantly, paclitaxel clearance varies among individuals, primarily because of genetic polymorphisms. This metabolic variability arises from a nonlinear process that is influenced by multiple single nucleotide polymorphisms (SNPs). Conventional bioinformatics methods struggle to accurately analyze this complex process and, currently, there is no established efficient algorithm for investigating SNP interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed a novel machine-learning approach called GEP-CSIs data mining algorithm. This algorithm, an advanced version of GEP, uses linear algebra computations to handle discrete variables. The GEP-CSI algorithm calculates a fitness function score based on paclitaxel clearance data and genetic polymorphisms in patients with nonsmall cell lung cancer. The data were divided into a primary set and a validation set for the analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified and validated 1184 three-SNP combinations that had the highest fitness function values. Notably, <i>SERPINA1</i>, <i>ATF3</i> and <i>EGF</i> were found to indirectly influence paclitaxel clearance by coordinating the activity of genes previously reported to be significant in paclitaxel clearance. Particularly intriguing was the discovery of a combination of three SNPs in genes <i>FLT1</i>, <i>EGF</i> and <i>MUC16</i>. These SNPs-related proteins were confirmed to interact with each other in the protein–protein interaction network, which formed the basis for further exploration of their functional roles and mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We successfully developed an effective deep-learning algorithm tailored for the nuanced mining of SNP interactions, leveraging data on paclitaxel clearance and individual genetic polymorphisms.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140914783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone deacetylase 6 as a novel promising target to treat cardiovascular disease","authors":"Ya-Xi Wu,&nbsp;Bing-Qian Li,&nbsp;Xiao-Qian Yu,&nbsp;Yu-Lin Liu,&nbsp;Rui-Hao Chui,&nbsp;Kai Sun,&nbsp;Dian-Guang Geng,&nbsp;Li-Ying Ma","doi":"10.1002/cai2.114","DOIUrl":"https://doi.org/10.1002/cai2.114","url":null,"abstract":"<p>Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.</p>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140881007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a disulfidptosis-related prognostic signature for prediction of the effect of treatment in patients with endometrial carcinoma","authors":"Lu Peng,&nbsp;Yuan Gao,&nbsp;Zifeng Cao,&nbsp;Yingxin Pang","doi":"10.1002/cai2.120","DOIUrl":"https://doi.org/10.1002/cai2.120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Disulfide, an essential compounds family, has diverse biological activity and can affect the dynamic balance between physiological and pathological states. A recently published study found that aberrant accumulation of disulfide had a lethal effect on cells. This mechanism of cell death, named disulfidptosis, differs from other known cell death mechanisms, including cuproptosis, apoptosis, necroptosis, and pyroptosis. The relationship between disulfidptosis and development of cancer, in particular endometrial carcinoma, remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this knowledge gap, we performed a preliminary analysis of samples from The Cancer Genome Atlas database. The samples were divided equally into a training group and a test group. A total of 2308 differentially expressed genes were extracted, and 11 were used to construct a prognostic model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Based on the risk score calculated using the prognostic model, the samples were divided into a high-risk group and a low-risk group. Survival time, tumor mutation burden, and microsatellite instability scores differed significantly between the two groups. Furthermore, a between-group difference in treatment effect was predicted. Comparison with other models in the literature indicated that this prognostic model had better predictive anility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results of this study provide a general framework for understanding the relationship between disulfidptosis and endometrial cancer that could be used for clinical evaluation and selection of appropriate personalized treatment strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140639631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non-small cell lung cancer","authors":"Jing Chen,&nbsp;Jing Yang,&nbsp;Yufang Liu,&nbsp;Xu Zhao,&nbsp;Juanjuan Zhao,&nbsp;Lin Tang,&nbsp;Mengmeng Guo,&nbsp;Ya Zhou,&nbsp;Chao Chen,&nbsp;Dongmei Li,&nbsp;Zhenke Wen,&nbsp;Guiyou Liang,&nbsp;Lin Xu","doi":"10.1002/cai2.117","DOIUrl":"https://doi.org/10.1002/cai2.117","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients: A meta-analysis","authors":"Huiyi Liu,&nbsp;Lu Fu,&nbsp;Shuyu Jin,&nbsp;Xingdong Ye,&nbsp;Yanlin Chen,&nbsp;Sijia Pu,&nbsp;Yumei Xue","doi":"10.1002/cai2.116","DOIUrl":"https://doi.org/10.1002/cai2.116","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>With the emergence of cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors, the outcomes of patients with malignant tumors have improved significantly. However, the incidence of cardiovascular adverse events has also increased, which can affect tumor treatment. In this study, we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Randomized clinical trials published in English from January 1, 2013, to November 30, 2022, were searched using the Cochrane Library and PubMed databases. All included trials examined all grade and grades 3–5 cardiac and vascular adverse events. These involved comparisons of CTLA-4 inhibitors to placebo, CTLA-4 inhibitors plus chemotherapy to chemotherapy alone, CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone, and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 20 trials were included. CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity (OR = 1.33, 95% CI: 1.00–1.75, <i>p</i> = 0.05). The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors (OR = 1.73, 95% CI: 1.13–2.65, <i>p</i> = 0.01), as well as the incidence rate of grades 3–5 cardiovascular adverse events (OR = 2.00, 95% CI: 1.08–3.70, <i>p</i> = 0.03). Compared with the non-CTLA-4 inhibitor group, CTLA-4 inhibitors plus chemotherapy, PD-1/PD-L1 inhibitors, or target agent did not significantly affect the incidence of cardiac and vascular toxicity. The incidence of grades 3–5 cardiac failure, hypertension, pericardial effusion, myocarditis, and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor, but the data were not statistically significant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings suggest that the incidence rate of all cardiovascular toxicity and severe cardiovascular toxicity increased in patients who were administered CTLA-4 inhibitors. In addition, the risk of serious cardiovascular toxic events was independent of the type of adverse event. From these results, physicians should assess the benefits and risks of CTLA-4 inhibitors when treating malignanc","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires","authors":"Yulin Xu,&nbsp;Wei Shan,&nbsp;Qian Luo,&nbsp;Meng Zhang,&nbsp;Dawei Huo,&nbsp;Yijin Chen,&nbsp;Honghu Li,&nbsp;Yishan Ye,&nbsp;Xiaohong Yu,&nbsp;Yi Luo,&nbsp;He Huang","doi":"10.1002/cai2.118","DOIUrl":"https://doi.org/10.1002/cai2.118","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR β-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V–J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140552821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes","authors":"Sahil Seth,&nbsp;Runzhe Chen,&nbsp;Yang Liu,&nbsp;Junya Fujimoto,&nbsp;Lingzhi Hong,&nbsp;Alexandre Reuben,&nbsp;Susan Varghese,&nbsp;Carmen Behrens,&nbsp;Tina McDowell,&nbsp;Luisa Solis Soto,&nbsp;Cara Haymaker,&nbsp;Annikka Weissferdt,&nbsp;Neda Kalhor,&nbsp;Jia Wu,&nbsp;Xiuning Le,&nbsp;Natalie I Vokes,&nbsp;Chao Cheng,&nbsp;John V. Heymach,&nbsp;Don L. Gibbons,&nbsp;P. Andrew Futreal,&nbsp;Ignacio I. Wistuba,&nbsp;Humam Kadara,&nbsp;Jianhua Zhang,&nbsp;Cesar Moran,&nbsp;Jianjun Zhang","doi":"10.1002/cai2.112","DOIUrl":"https://doi.org/10.1002/cai2.112","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma-like components. The molecular and immune landscape of PSC has not been well defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel, whole-exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In total, 27 canonical cancer gene mutations were identified, with <i>TP53</i> the most frequently mutated gene, followed by <i>KRAS</i>. Interestingly, most <i>TP53</i> and KRAS mutations were earlier genomic events mapped to the trunks of the tumors, suggesting branching evolution in most PSC tumors. We identified two distinct molecular subtypes of PSC, driven primarily by immune infiltration and signaling. The Immune High (IM-H) subtype was associated with superior survival, highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis. IM-H tumors were associated with favorable recurrence-free survival and overall survival, highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140552053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}