Cancer Science最新文献_第4页

Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors. 新辅助化疗前后三阴性乳腺癌肿瘤的基因组和转录组分析。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-10-07 DOI: 10.1111/cas.16339

Tomomi Nishimura, Ravi Velaga, Norikazu Masuda, Kosuke Kawaguchi, Shuji Kawaguchi, Masahiro Takada, Yurina Maeshima, Sunao Tanaka, Yuichiro Kikawa, Takayuki Kadoya, Hiroko Bando, Rikiya Nakamura, Yutaka Yamamoto, Takayuki Ueno, Hiroyuki Yasojima, Hiroshi Ishiguro, Satoshi Morita, Shinji Ohno, Hironori Haga, Fumihiko Matsuda, Seishi Ogawa, Masakazu Toi

{"title":"Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors.","authors":"Tomomi Nishimura, Ravi Velaga, Norikazu Masuda, Kosuke Kawaguchi, Shuji Kawaguchi, Masahiro Takada, Yurina Maeshima, Sunao Tanaka, Yuichiro Kikawa, Takayuki Kadoya, Hiroko Bando, Rikiya Nakamura, Yutaka Yamamoto, Takayuki Ueno, Hiroyuki Yasojima, Hiroshi Ishiguro, Satoshi Morita, Shinji Ohno, Hironori Haga, Fumihiko Matsuda, Seishi Ogawa, Masakazu Toi","doi":"10.1111/cas.16339","DOIUrl":"https://doi.org/10.1111/cas.16339","url":null,"abstract":"Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leveraging non-coding regions to guarantee the accuracy of small-sized panel-based tumor mutational burden estimates. 利用非编码区保证基于小样本组的肿瘤突变负荷估计的准确性。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-10-01 DOI: 10.1111/cas.16342

Takahiro Nishino, Mio Yumura, Kuniko Sunami, Takashi Kubo, Hitoshi Ichikawa, Tomoyo Yasuda, Eisaku Furukawa, Momoko Nagai, Yasushi Yatabe, Mamoru Kato, Takashi Kohno

{"title":"Leveraging non-coding regions to guarantee the accuracy of small-sized panel-based tumor mutational burden estimates.","authors":"Takahiro Nishino, Mio Yumura, Kuniko Sunami, Takashi Kubo, Hitoshi Ichikawa, Tomoyo Yasuda, Eisaku Furukawa, Momoko Nagai, Yasushi Yatabe, Mamoru Kato, Takashi Kohno","doi":"10.1111/cas.16342","DOIUrl":"https://doi.org/10.1111/cas.16342","url":null,"abstract":"Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA. SNRPB2通过控制MDM4前mRNA的替代剪接促进三阴性乳腺癌的进展。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-27 DOI: 10.1111/cas.16356

Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun

{"title":"SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.","authors":"Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun","doi":"10.1111/cas.16356","DOIUrl":"https://doi.org/10.1111/cas.16356","url":null,"abstract":"Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic single-cell sequencing unveils the tumor microenvironment evolution of gastric cancer abdominal wall metastases during radiotherapy. 动态单细胞测序揭示放疗期间胃癌腹壁转移灶的肿瘤微环境演变

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-26 DOI: 10.1111/cas.16308

Qianqian Mao, Zhenzhen Wu, Yonghong Lai, Ling Wang, Qiongzhi Zhao, Xi Xu, Xiansheng Lu, Wenjun Qiu, Zhihua Zhang, Jiani Wu, Gaofeng Wang, Rui Zhou, Jianhua Wu, Huiying Sun, Na Huang, Xiatong Huang, Luyang Jiang, Yiran Fang, Yuyun Kong, Li Liang, Jianping Bin, Yulin Liao, Min Shi, Wangjun Liao, Dongqiang Zeng

{"title":"Dynamic single-cell sequencing unveils the tumor microenvironment evolution of gastric cancer abdominal wall metastases during radiotherapy.","authors":"Qianqian Mao, Zhenzhen Wu, Yonghong Lai, Ling Wang, Qiongzhi Zhao, Xi Xu, Xiansheng Lu, Wenjun Qiu, Zhihua Zhang, Jiani Wu, Gaofeng Wang, Rui Zhou, Jianhua Wu, Huiying Sun, Na Huang, Xiatong Huang, Luyang Jiang, Yiran Fang, Yuyun Kong, Li Liang, Jianping Bin, Yulin Liao, Min Shi, Wangjun Liao, Dongqiang Zeng","doi":"10.1111/cas.16308","DOIUrl":"https://doi.org/10.1111/cas.16308","url":null,"abstract":"Although the combination of immunotherapy and radiotherapy (RT) for the treatment of malignant tumors has shown rapid development, the insight of how RT remodels the tumor microenvironment to prime antitumor immunity involves a complex interplay of cell types and signaling pathways, much of which remains to be elucidated. Four tumor samples were collected from the same abdominal wall metastasis site of the patient with gastric cancer at baseline and during fractionated RT for single-cell RNA and T-cell receptor sequencing. The Seurat analysis pipeline and immune receptor analysis were used to characterize the gastric cancer metastasis ecosystem and investigated its dynamic changes of cell proportion, cell functional profiles and cell-to-cell communication during RT. Immunohistochemical and immunofluorescent staining and bulk RNA sequencing were applied to validate the key results. We found tumor cells upregulated immune checkpoint genes in response to RT. The infiltration and clonal expansion of T lymphocytes declined within tumors undergoing irradiation. Moreover, RT led to the accumulation of proinflammatory macrophages and natural killer T cells with enhanced cytotoxic gene expression signature. In addition, subclusters of dendritic cells and endothelial cells showed decrease in the expression of antigen present features in post-RT samples. More ECM component secreted by myofibroblasts during RT. These findings indicate that RT induced the dynamics of the immune response that should be taken into consideration when designing and clinically implementing innovative multimodal cancer treatment regimens of different RT and immunotherapy approaches.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity. USP10 的缺失通过抑制 LKB1 的活性调节丝氨酸合成途径，从而促进肝细胞癌的增殖。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-26 DOI: 10.1111/cas.16336

Chi Ma, Zhikun Lin, Jiaqi Yao, Wangshu Qin, Xiaolin Wang, Qi Li, Yaorui Ye, Xinyu Liu, Fating Chen, Jinlong Hu, Guowang Xu, Guang Tan

{"title":"Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity.","authors":"Chi Ma, Zhikun Lin, Jiaqi Yao, Wangshu Qin, Xiaolin Wang, Qi Li, Yaorui Ye, Xinyu Liu, Fating Chen, Jinlong Hu, Guowang Xu, Guang Tan","doi":"10.1111/cas.16336","DOIUrl":"https://doi.org/10.1111/cas.16336","url":null,"abstract":"Metabolic dysregulation is emerging as a critical factor in tumorigenesis, and reprogramming of serine metabolism has been identified as an essential factor in the progression of hepatocellular carcinoma (HCC). Studies have shown that LKB1 deficiency can activate mTOR to upregulate the serine synthesis pathway (SSP) and promote tumor progression. Our team discovered that ubiquitin-specific protease 10 (USP10) can inhibit HCC proliferation through mTOR, but its relationship with SSP needs further investigation. The metabolite assays revealed a significant increase in serine content in HCC tissues. Through the LKB1/mTOR/activating transcription factor 4 (ATF4) axis, loss of USP10 may increase serine biosynthesis and promote the proliferation of HCC in vitro and in vivo. Furthermore, it was found that USP10 could activate LKB1 through deubiquitination. Analyzing clinical HCC tissues revealed a positive correlation between USP10 and LKB1. Additionally, those with high expression of USP10 in HCC tissues showed a better degree of tumor differentiation and longer overall survival time. Moreover, we found increased expression of both serine and its synthase in liver tumor tissues of USP10 liver-specific KO mice. Loss of USP10 inhibits the activity of LKB1, contributing to the stimulation of the mTOR/ATF4 axis and SSP and then promoting the proliferation of HCC. This work presents a novel approach for serine-targeted treatment in HCC.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study. KEAP1-NRF2系统变异患者的特定癌症类型和预后：一项回顾性队列研究。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-26 DOI: 10.1111/cas.16355

Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka

{"title":"Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study.","authors":"Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka","doi":"10.1111/cas.16355","DOIUrl":"https://doi.org/10.1111/cas.16355","url":null,"abstract":"The KEAP1-NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C-CAT database, which contains the gene-panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1-NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selective killing of castration-resistant prostate cancer cells by formycin A via the ATF4-CHOP axis. 甲霉素 A 通过 ATF4-CHOP 轴选择性杀死耐阉割前列腺癌细胞

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-26 DOI: 10.1111/cas.16349

Tomoki Takei, Yuki Hamamura, Hiroshi Hongo, Etsu Tashiro, Masaya Imoto, Takeo Kosaka, Mototsugu Oya

引用次数: 0

Decreased PU.1 expression in mature B cells induces lymphomagenesis. 成熟 B 细胞中 PU.1 表达减少会诱发淋巴瘤。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-25 DOI: 10.1111/cas.16344

Shinya Endo, Nao Nishimura, Kosuke Toyoda, Yoshihiro Komohara, Joaquim Carreras, Hiromichi Yuki, Takafumi Shichijo, Shikiko Ueno, Niina Ueno, Shinya Hirata, Yawara Kawano, Kisato Nosaka, Masashi Miyaoka, Naoya Nakamura, Ai Sato, Kiyoshi Ando, Hiroaki Mitsuya, Koichi Akashi, Daniel G Tenen, Jun-Ichirou Yasunaga, Masao Matsuoka, Yutaka Okuno, Hiro Tatetsu

{"title":"Decreased PU.1 expression in mature B cells induces lymphomagenesis.","authors":"Shinya Endo, Nao Nishimura, Kosuke Toyoda, Yoshihiro Komohara, Joaquim Carreras, Hiromichi Yuki, Takafumi Shichijo, Shikiko Ueno, Niina Ueno, Shinya Hirata, Yawara Kawano, Kisato Nosaka, Masashi Miyaoka, Naoya Nakamura, Ai Sato, Kiyoshi Ando, Hiroaki Mitsuya, Koichi Akashi, Daniel G Tenen, Jun-Ichirou Yasunaga, Masao Matsuoka, Yutaka Okuno, Hiro Tatetsu","doi":"10.1111/cas.16344","DOIUrl":"https://doi.org/10.1111/cas.16344","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non-Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non-germinal center B-cell-like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1-Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B-cell lymphomas. In contrast, no wild-type mice developed B-cell lymphoma. In addition, RNA-seq analysis of lymphoma cells from Cγ1-Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral-transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B-cell lymphoma development.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy. 宿主 ANGPTL2 可建立免疫抑制性肿瘤微环境，并对免疫检查点疗法产生抗药性。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-25 DOI: 10.1111/cas.16348

Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike

{"title":"Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.","authors":"Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike","doi":"10.1111/cas.16348","DOIUrl":"https://doi.org/10.1111/cas.16348","url":null,"abstract":"Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor \"immunophenotypes\" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models. 在胰腺癌模型中使用与单甲基金丝桃素 E 或德鲁替康结合的抗组织因子抗体。

IF 5.7 2区医学

Cancer Science Pub Date : 2024-09-25 DOI: 10.1111/cas.16335

Ryo Tsumura, Takahiro Anzai, Yoshikatsu Koga, Hiroki Takashima, Yasuhiro Matsumura, Masahiro Yasunaga

{"title":"Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models.","authors":"Ryo Tsumura, Takahiro Anzai, Yoshikatsu Koga, Hiroki Takashima, Yasuhiro Matsumura, Masahiro Yasunaga","doi":"10.1111/cas.16335","DOIUrl":"https://doi.org/10.1111/cas.16335","url":null,"abstract":"Antibody-drug conjugates (ADCs) have been recognized as a promising class of cancer therapeutics. Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021. However, the feasibility of other payloads in the design of anti-TF ADCs is still unclear because no reports have compared payloads with different cytotoxic mechanisms. For ADCs targeting other antigens, such as Her2, optimizing the payload is also an important issue in order to improve in vivo efficacy. In this study, we prepared humanized anti-TF Ab (clone.1084) conjugated with monomethyl auristatin E (MMAE) or deruxtecan (DXd), and evaluated the efficacy in several cell line- and patient-derived xenograft models of pancreatic cancer. As a result, optimizing the drug / Ab ratio was necessary for each payload in order to prevent pharmacokinetic deterioration and maximize delivery efficiency. In addition, MMAE-conjugated anti-TF ADC showed higher antitumor effects in tumors with strong and homogeneous TF expression, while DXd-conjugated anti-TF ADC was more effective in tumors with weak and heterogeneous TF expression. Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0