Cancer Science最新文献

{"title":"RETRACTION: Role of the MUC1-C Oncoprotein in the Acquisition of Cisplatin Resistance by Urothelial Carcinoma","authors":"","doi":"10.1111/cas.70016","DOIUrl":"10.1111/cas.70016","url":null,"abstract":"<p><b>RETRACTION:</b> K. Shigeta, M. Hasegawa, E. Kikuchi, Y. Yasumizu, T. Kosaka, R. Mizuno, S. Mikami, A. Miyajima, D. Kufe and M. Oya, “Role of the MUC1-C Oncoprotein in the Acquisition of Cisplatin Resistance by Urothelial Carcinoma,” <i>Cancer Science</i> 111, no. 10 (2020): 3639–3652, https://doi.org/10.1111/cas.14574.</p><p>The above article, published online on 16 July 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley &amp; Sons Australia Ltd. The retraction has been agreed upon due to several instances of duplications of western blot bands observed between Figures 2E and 3B; 4A and 4D; S1b and S3a; and within S1d. The authors commented that this was due to inadvertent errors and provided some data including replacement images. However, the data supplied did not meet acceptable standards for raw data and the editors were not satisfied with the explanation provided. Due to the extent of the errors, the editors have lost confidence in the results and conclusions of this study. The authors disagree with the retraction.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"1154"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGFR2/3 Gene Alterations and Clinical Outcomes in Advanced/Metastatic Urothelial Cancer in Japan: MONSTAR-SCREEN Database Study","authors":"Nobuaki Matsubara,&nbsp;Takahiro Osawa,&nbsp;Takashige Abe,&nbsp;Mototsugu Oya,&nbsp;Koshiro Nishimoto,&nbsp;Toshiyuki Iwahori,&nbsp;Hiroaki Tsuchiya,&nbsp;Maiko Murota,&nbsp;Masaki Yoshida,&nbsp;Yohei Tatematsu,&nbsp;Yosuke Nakano,&nbsp;Masatoshi Eto,&nbsp;Norio Nonomura","doi":"10.1111/cas.70000","DOIUrl":"10.1111/cas.70000","url":null,"abstract":"<p>Advanced/metastatic urothelial cancer (a/m UC) still has a poor prognosis despite the recent medical advances. Recent studies demonstrated that fibroblast growth factor receptor (<i>FGFR</i>) gene alterations (GAs) may be driver genes for UC; however, the proportion of UC genetic panel testing in Japan remains low. We clarified the proportion of patients with <i>FGFR2/3</i> GAs, treatment patterns, and clinical outcomes in a/m UC patients in Japan. This study was a descriptive epidemiological study using the MONSTAR-SCREEN database, and 138 patients with a/m UC were evaluated. The primary endpoint was the proportion of patients with <i>FGFR2/3</i> GAs. The secondary endpoints included treatment patterns, clinical outcomes, genomic status before and after treatment, etc. The proportion of <i>FGFR</i> GA-positive patients in a/m UC was 11.9%. The most common <i>FGFR</i> mutation variant and fusion gene were S249C (4.4%) and <i>FGFR3-TACC3</i> fusion (3.7%), respectively. Fifty-one patients were tested two or more times; a few changes were observed in the <i>FGFR</i> GA status, regardless of the treatment regimen. Co-occurrence association was observed in <i>FGFR1</i> with <i>TET2</i>, and in <i>FGFR3</i> with <i>CHEK2</i> or <i>MLL2</i>. During the first-, second-, and third-line treatment, median progression-free survival (PFS) of GA-positive patients was 7.3, 2.9, and 6.2 months, while for GA-negative patients, 6.9, 3.1, and 6.9 months, respectively. This study revealed that one in eight a/m UC patients had <i>FGFR2/3</i> GAs, and a few changes were observed in <i>FGFR</i> GA status before and after treatment. Genetic testing will be beneficial for the selection of appropriate treatments after a diagnosis of a/m UC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 5","pages":"1424-1432"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second Opinion Referrals of Cancer Patients in Japan—A Nationwide Study","authors":"Mieko Takasawa,&nbsp;Norihiro Teramoto,&nbsp;Natsumi Yamashita,&nbsp;Takahiro Higashi","doi":"10.1111/cas.70012","DOIUrl":"10.1111/cas.70012","url":null,"abstract":"<p>Seeking a second opinion (SO) is a patient's right that is essential to appropriate decision-making for their care and treatment. In Japan, however, no previous studies have provided objective data on the nationwide practice of SO among cancer patients. In this study, we investigated SO referrals, including delays in initiating care, using data from nationwide hospital-based cancer registries and 2018–2020 the Diagnosis Procedure Combination (DPC) survey. Among the more than 2.6 million patients diagnosed with cancer, 1.6% received SO referral letters as reimbursement. The referral rates varied based on sex, age, and geographic regions. A total of 52.1% of SO were sought before active treatment of the tumor. Approximately 60% of the patients who sought SO prior to the initial treatment returned to their original provider for treatment. The average period from diagnosis to the start of treatment among those who sought SO was 18 days and 22 days longer for non-small lung cancer and breast cancer, respectively, than among those who did not seek SO. In the future, the risk–benefit of SO referral should be examined, considering both the prognostic impact of treatment delay due to SO and the psychological benefits for the patient gained from SO.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 5","pages":"1417-1423"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-Time, AI-Guided Photodynamic Laparoscopy Enhances Detection in a Rabbit Model of Peritoneal Cancer Metastasis","authors":"Adriana Rivera-Piza,&nbsp;Sung-Ho Lee,&nbsp;Hannah HeeJung Lee,&nbsp;Seungho Lee,&nbsp;Su-Jin Shin,&nbsp;Jaehyuk Kim,&nbsp;Jong-Hyun Park,&nbsp;Jae Eun Yu,&nbsp;Sang Won Lee,&nbsp;Gyuri Park,&nbsp;Brian C. Wilson,&nbsp;Hyoung-Il Kim","doi":"10.1111/cas.70009","DOIUrl":"10.1111/cas.70009","url":null,"abstract":"<p>Accurate diagnosis is essential for effective cancer treatment, particularly in peritoneal surface malignancies, where failure to detect metastatic lesions can mislead the treatment plan. This study assessed the diagnostic accuracy of staging laparoscopy using the integration of artificial intelligence (AI)-guided photodynamic diagnosis (PDD) with the photosensitizer Phonozen, activated at 405 nm in a rabbit model. To create peritoneal carcinomatosis, VX2 cells were inoculated laparoscopically into the peritoneum of female white New Zealand rabbits. Conventional and PDD-guided laparoscopy utilized a customized light source that emitted broad-spectrum white light or 405-nm blue light, respectively. The surgical procedure comprised a tripartite approach: exploration and labeling of suspected nodules under white-light visualization, identification of additional metastatic tumors under blue-excitation fluorescent light, and confirmatory open laparotomy to locate overlooked nodules by palpation. Our results showed that the initial experimental data from 371 nodules in 14 rabbits, comparing conventional diagnostic laparoscopy and PDD, showed increased detection sensitivity from 67% ± 1.9% (conventional) to 98% ± 0.7% (PDD) in the small-size nodule. In the second experimental data set from 265 nodules in 10 rabbits, the addition of a real-time AI algorithm further increased the sensitivity to 100% ± 0.0%. Combining PDD with AI enhances the detection of peritoneal cancer metastasis in staging laparoscopy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"966-975"},"PeriodicalIF":4.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline Pathogenic Variants and Clinical Outcomes in Asian Patients With Breast Cancer","authors":"Rui Kitadai,&nbsp;Shu Yazaki,&nbsp;Aya Kuchiba,&nbsp;Takashi Yamanaka,&nbsp;Sho Shiino,&nbsp;Chisako Yamauchi,&nbsp;Kenichi Harano,&nbsp;Motonobu Saito,&nbsp;Yosuke Hirotsu,&nbsp;Hisaki Aiba,&nbsp;Teruhiko Yoshida,&nbsp;Ryuji Hamamoto,&nbsp;Chikako Shimizu,&nbsp;Akihiko Shimomura,&nbsp;Yuki Kojima,&nbsp;Tatsunori Shimoi,&nbsp;Yukihide Momozawa,&nbsp;Kazuki Sudo,&nbsp;Masayuki Yoshida,&nbsp;Kuniko Sunami,&nbsp;Megumi Hori,&nbsp;Kota Katanoda,&nbsp;Yoko Shimada,&nbsp;Yuji Yamashita,&nbsp;Takahiro Kogawa,&nbsp;Takeshi Murata,&nbsp;Saori Fujiwara,&nbsp;Yohei Miyagi,&nbsp;Hiroshi Nakagomi,&nbsp;Kazunoshin Tachibana,&nbsp;Masao Omata,&nbsp;Tohru Ohtake,&nbsp;Akihiko Suto,&nbsp;Tatsuya Onishi,&nbsp;Yoichi Naito,&nbsp;Toshinari Yamashita,&nbsp;Kan Yonemori,&nbsp;Takashi Kohno,&nbsp;Kouya Shiraishi","doi":"10.1111/cas.70002","DOIUrl":"10.1111/cas.70002","url":null,"abstract":"<p>Despite the importance of genetic testing for risk assessment and treatment in breast cancer, the prognostic impact of germline pathogenic variants (PVs), especially in Asian populations, is unclear. We assessed the impact of germline PVs in patients with early-stage breast cancer. This study included 7278 Japanese multihospital registry patients. PVs of <i>ATM</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>CDH1</i>, <i>CHEK2</i>, <i>NBN</i>, <i>NF1</i>, <i>PALB2</i>, <i>PTEN</i>, <i>STK11</i>, and <i>TP53</i> were evaluated. PV and non-PV carriers were matched by age, histology, and stage. Associations between PVs and survival were assessed. The primary outcome was invasive disease-free survival (IDFS). Secondary outcomes included relapse-free survival (RFS), overall survival, and breast cancer-specific survival. We identified 320 (4.4%) patients with <i>BRCA1/2</i> PVs and 79 (1.1%) with PVs other than <i>BRCA1/2</i> (non-<i>BRCA1/2</i>). A total of 360 patients (<i>BRCA1/2</i>, <i>n</i> = 289; non-<i>BRCA1/2</i>, <i>n</i> = 71) were matched to 720 noncarriers. Patients with <i>BRCA1/2</i> PVs had significantly shorter 10-year IDFS (adjusted hazard ratio (aHR) = 2.15; 95% confidence interval (CI), 1.61–2.86; <i>p</i> &lt; 0.001); and RFS (aHR = 1.74; 95% CI, 1.25–2.44; <i>p</i> = 0.001) than noncarriers. Among patients with hormone receptor-positive HER2-negative breast cancer, <i>BRCA1/2</i> PV carriers exhibited significantly shorter 10-year IDFS than noncarriers, even those with stage I/II disease (total, aHR = 2.23; 95% CI, 1.55–3.23; <i>p</i> &lt; 0.001, Stage I/II, aHR = 2.22; 95% CI, 1.43–3.44; <i>p</i> &lt; 0.001). There was no significant difference in 10-year IDFS between the non-<i>BRCA1/2</i> PV carrier and noncarrier groups (aHR = 1.40; 95% CI, 0.67–2.93; <i>p</i> = 0.37). Asian patients with breast cancer carrying germline <i>BRCA1/2</i> PV, even those with a low recurrence risk, have significantly shorter 10-year IDFS than noncarriers.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"1048-1058"},"PeriodicalIF":4.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Clinical and Molecular Characterization of Distinct Subtypes in Adult T Cell Acute Lymphoblastic Leukemia","authors":"Heye Yu,&nbsp;Wenbing Liu,&nbsp;Junping Zhang,&nbsp;Leling Xie,&nbsp;Anli Lai,&nbsp;Zheng Tian,&nbsp;Kejing Tang,&nbsp;Haiyan Xing,&nbsp;Ying Wang,&nbsp;Hui Wei,&nbsp;Qing Rao,&nbsp;Runxia Gu,&nbsp;Min Wang,&nbsp;Huijun Wang,&nbsp;Jianxiang Wang,&nbsp;Shaowei Qiu","doi":"10.1111/cas.70010","DOIUrl":"10.1111/cas.70010","url":null,"abstract":"<p>T-cell acute lymphoblastic leukemia (T-ALL) is a clonal proliferative malignant disease characterized by abnormal T-cell development. The classification of T-ALL primarily hinges on immunophenotype, encompassing early T-cell precursor (ETP)-ALL, near-ETP-ALL, and non-ETP-ALL. We summarized clinical information from 117 patients, with genetic data available for 77 patients and transcriptomic data available for 24 patients. An ETP-like score model was established based on transcriptome, aiming to address the subjectivity in the current T-ALL immunophenotype classification. The retrospective analysis indicated that ETP immunophenotype was not a prognostic factor for T-ALL patients. Compared to non-ETP-ALL patients, ETP-like patients including ETP-ALL and near-ETP-ALL were more likely to carry <i>MED12</i> gene mutations, which may predict a dismal outcome. Transcriptomic analysis suggested that T-ALL patients with different immunophenotypes were in accordance with the T-cell development trajectory, while ETP-like patients exhibited characteristics of early T-cell development. Finally, we established an ETP-like score model and confirmed its efficiency across four independent cohorts, with sensitivity exceeding 80%. And T-ALL patients with high ETP-like score were associated with poor prognosis. In conclusion, our study elucidated the clinical and molecular features of distinct subtypes of T-ALL patients, providing new valuable insights for T-ALL classification.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"1126-1138"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal Vessels Potentially Accelerate Glioblastoma Proliferation by Inducing the Protumor Activation of Macrophages","authors":"Hiroaki Matsuzaki,&nbsp;Keitaro Kai,&nbsp;Yoshihiro Komohara,&nbsp;Hiromu Yano,&nbsp;Cheng Pan,&nbsp;Yukio Fujiwara,&nbsp;Rin Yamada,&nbsp;Ai Iwauchi,&nbsp;Nei Fukasawa,&nbsp;Toshihide Tanaka,&nbsp;Masayuki Shimoda,&nbsp;Hiroshi Watanabe,&nbsp;Toru Maruyama,&nbsp;Toru Takeo,&nbsp;Yoshiki Mikami,&nbsp;Akitake Mukasa","doi":"10.1111/cas.70014","DOIUrl":"10.1111/cas.70014","url":null,"abstract":"<p>Glioblastoma (GBM) involves disruptions in the blood–brain barrier (BBB) and alterations in the immune microenvironment, including the activation of glioma-associated macrophages (GAMs). Vascular endothelial growth factor inhibitors, commonly used in recurrent GBM treatment, can influence these processes. This study investigates the relationship between BBB disruption and GAM activation, focusing on plasmalemma vesicle-associated protein (PLVAP), a marker of BBB disruption, and α1-acid glycoprotein (AGP), an inflammatory protein implicated in tumor progression. PLVAP expression was analyzed by immunohistochemistry (IHC) in human GBM samples to determine correlations with tumor grade, proliferation, and GAM activation. Pre- and post-bevacizumab treatment GBM samples were compared to assess changes in BBB integrity and macrophage activity. AGP's role in GAM activation was studied through in vitro assays and glioma implantation in AGP knockout mice, with assessments of tumor growth and angiogenesis. Results showed elevated PLVAP expression in higher-grade gliomas, correlating with increased tumor proliferation and GAM activation, particularly around PLVAP-positive vessels. Bevacizumab treatment reduced PLVAP expression and macrophage activity. AGP localized to regions of BBB disruption, promoting macrophage-mediated tumor growth in vitro. AGP knockout mice demonstrated reduced angiogenesis and prolonged survival. Spatial analysis revealed increased expression of macrophage-inducing molecules near PLVAP-positive vessels. These findings suggest PLVAP as a marker of BBB disruption and glioma malignancy. AGP, associated with BBB leakage, contributes to GAM activation and tumor progression, highlighting its potential as a therapeutic target for GBM.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"897-909"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GD2 is a Crucial Ganglioside in the Signal Modulation and Application as a Target of Cancer Therapeutics","authors":"Koichi Furukawa,&nbsp;Yuhsuke Ohmi,&nbsp;Kazunori Hamamura,&nbsp;Yuki Ohkawa,&nbsp;Noboru Hashimoto,&nbsp;Orie Tajima,&nbsp;Kei Kaneko,&nbsp;Keiko Furukawa","doi":"10.1111/cas.70011","DOIUrl":"10.1111/cas.70011","url":null,"abstract":"<p>While various glycosphingolipids were identified as cancer-associated carbohydrate antigens to be used as tumor markers, disialylated gangliosides such as GD3 and GD2 have particularly attracted attention from many researchers as promising cancer-associated antigens. Simultaneously, their functions in cancer and normal tissues have also been reported. Although GD3 is expressed at the early neural developmental stage and in various cancers, it is also found in the activated status of some normal cells such as astrocytes and lymphocytes. On the other hand, GD2 is expressed in more restricted cells than GD3, enabling anti-GD2 immune therapy to be more applicable for immunotherapy. Recently, the expression of GD2 has been reported in various epithelial cancers and neuroectoderm-derived tumors. The involvement of GD2 in cancer stem cell propertiesand the roles of GD2 in the signal modulation to bring about cancer stemness are now some of the most fascinating research topics. Cancer immunotherapy targeting GD2 by anti-GD2 antibody or anti-GD2 CAR-T is now widely being challenged with various modifications such as combination with cytokines, chemotherapy, or immune checkpoint blocking.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"862-870"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-Dependent Cellular Cytotoxicity of iPS Cell-Derived Natural Killer T Cells by Anti-GD2 mAb for Neuroblastoma","authors":"Katsuhiro Nishimura,&nbsp;Takahiro Aoki,&nbsp;Midori Kobayashi,&nbsp;Mariko Takami,&nbsp;Ko Ozaki,&nbsp;Keita Ogawa,&nbsp;Wang Hongxuan,&nbsp;Daiki Shimizu,&nbsp;Daisuke Katsumi,&nbsp;Hiroko Yoshizawa,&nbsp;Shugo Komatsu,&nbsp;Tomozumi Takatani,&nbsp;Kiyoshi Hirahara,&nbsp;Haruhiko Koseki,&nbsp;Tomoro Hishiki,&nbsp;Shinichiro Motohashi","doi":"10.1111/cas.70008","DOIUrl":"10.1111/cas.70008","url":null,"abstract":"<p>While antibody-dependent cellular cytotoxicity (ADCC) by anti-disialoganglioside GD2 monoclonal antibody (mAb) has succeeded in increasing the survival rate of high-risk patients with neuroblastoma, approximately 40%–50% of patients die from the disease. Recently, we developed induced pluripotent stem cell-derived natural killer T (iPS-NKT) cells, which exhibit NK-like cytotoxicity. However, whether iPS-NKT cells can induce ADCC function is unclear. Here, we investigated the ADCC of iPS-NKT cells and the efficacy of the combination treatment of anti-GD2 mAb and iPS-NKT cells against neuroblastoma. Anti-GD2 mAb enhanced the cytotoxicity and secretion of cytokines and cytotoxic granules of iPS-NKT cells, which expressed CD16 to GD2-expressing neuroblastoma cell lines. We also examined which Fcγ receptors contribute to ADCC of iPS-NKT cells. CD16 stimulation against iPS-NKT cells caused cytotoxicity and secretion of interferon-gamma, tumor necrosis factor, and granzyme B. In contrast, CD32 and CD64 stimulation did not. In vivo, the intratumor administration of anti-GD2 mAb and iPS-NKT cells significantly inhibited tumor growth compared with the other treatment groups: no treatment, anti-GD2 mAb alone, and iPS-NKT cells alone. In conclusion, iPS-NKT cells exhibit CD16-mediated ADCC, and the addition of iPS-NKT cells to anti-GD2 mAb therapy may be a potential approach for immunotherapy against neuroblastoma.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"884-896"},"PeriodicalIF":4.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts","authors":"Takahiro Utsumi,&nbsp;Hayato Mizuta,&nbsp;Yosuke Seto,&nbsp;Ken Uchibori,&nbsp;Makoto Nishio,&nbsp;Isamu Okamoto,&nbsp;Ryohei Katayama","doi":"10.1111/cas.70006","DOIUrl":"10.1111/cas.70006","url":null,"abstract":"<p>Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) shows marked tumor shrinkage by ALK-tyrosine kinase inhibitors (TKIs). However, tumors almost inevitably relapse owing to the development of acquired resistance. Resistance mechanisms include secondary ALK mutations and the activation of bypass pathways, such as cMET, cKIT, or EGFR, though some remain unknown. In this study, we analyzed alectinib-resistant patient samples and identified a significant increase in AXL expression in the tumor, and a high level of GAS6, the ligand for AXL, in the pleural effusion. AXL-overexpressing H3122 ALK-rearranged NSCLC cells exhibited partial resistance to alectinib, which was enhanced by GAS6 supplementation but could be overcome by the ALK/AXL inhibitor gilteritinib. Moreover, GAS6-overexpressing NIH3T3 cells and AXL-expressing H3122 cells were subcutaneously injected into the left and right sides of nude mice simultaneously, followed by alectinib treatment. The supply of GAS6 from NIH3T3 may have accelerated tumor relapse under alectinib treatment. However, even without GAS6-overexpressing NIH3T3, AXL-overexpressing H3122 tumor relapsed within 1 month possibly due to increased host mouse Gas6 expression. Single-cell RNA sequencing revealed that specific cancer-associated fibroblasts (CAFs) and a subset of tumor-associated macrophages (TAMs) are the primary sources of Gas6 in the tumor microenvironment (TME). During alectinib treatment, TAMs increased their infiltration into the TME, whereas CAFs altered their expression patterns, substantially upregulating Mmp11. These findings suggest that AXL expression in resistant cancer cells, combined with increased Gas6 production in the TME, contributes to enhanced ALK-TKI resistance.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 4","pages":"1034-1047"},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}