Cancer Communications最新文献

{"title":"Efficacy and safety of first-line sintilimab plus anlotinib versus chemotherapy for metastatic non-small cell lung cancer: a phase II, open-label, randomized controlled trial","authors":"Tianqing Chu,&nbsp;Hua Zhong,&nbsp;Zhuang Yu,&nbsp;Jing Wang,&nbsp;Yanqiu Zhao,&nbsp;Xiaoqian Mu,&nbsp;Xinmin Yu,&nbsp;Xun Shi,&nbsp;Qingming Shi,&nbsp;Maojing Guan,&nbsp;Cuimin Ding,&nbsp;Nan Geng,&nbsp;Jialin Qian,&nbsp;Baohui Han","doi":"10.1002/cac2.12654","DOIUrl":"10.1002/cac2.12654","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The prognosis for non-small cell lung cancer (NSCLC) patients treated with standard platinum-based chemotherapy was suboptimal, with safety concerns. Following encouraging results from a preliminary phase I study, this phase II trial investigated the efficacy and safety of first-line sintilimab and anlotinib in metastatic NSCLC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this open-label, randomized controlled trial (NCT04124731), metastatic NSCLC without epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or proto-oncogene tyrosine-protein kinase ROS (ROS1) mutations, and previous treatments for metastatic disease were enrolled. Participants were randomly assigned in a 1:1 ratio to either sintilimab (200 mg every 3 weeks) plus anlotinib (12 mg D1-14 every 3 weeks) or a standard platinum-based chemotherapy regimen. Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression. The primary endpoint was the objective response rate (ORR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>From November 2019 to March 2023, 99 patients were randomized into the sintilimab plus anlotinib group (<i>n</i> = 49) and the chemotherapy group (<i>n</i> = 50). The ORR was significantly higher in the sintilimab plus anlotinib group (44.9%; 95% confidence interval [CI] = 30.7%-59.8%) compared to the chemotherapy group (18.0%; 95% CI = 8.6%-31.4%, <i>P</i> = 0.003). Progression-free survival (PFS) was also notably longer (median: 14.4 vs. 5.6 months; hazard ratio [HR] = 0.39; 95% CI = 0.23-0.67; <i>P</i> &lt; 0.001). The 24-month overall survival rate was 58.4% (95% CI = 40.4%-72.6%) and 43.2% (95% CI = 26.0%-59.2%), respectively. The rate of grade 3 or higher treatment-related adverse events was lower in the sintilimab plus anlotinib group (28.0%) than in the chemotherapy group (49.0%), especially for the hematological toxicities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>First-line sintilimab plus anlotinib showed improved ORR and PFS, alongside a superior safety profile, compared to the standard platinum-based chemotherapy for metastatic NSCLC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"442-455"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12654","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression profiling of primary and metastatic oral squamous cell carcinoma identifies progression-associated transcriptome changes and therapeutic vulnerabilities","authors":"Jonas Pyko,&nbsp;Markus Glaß,&nbsp;Julia Rosemann,&nbsp;Matthias Kappler,&nbsp;Jana Macho,&nbsp;Sarah Qasem,&nbsp;Stefan Hüttelmaier,&nbsp;Alexander W. Eckert,&nbsp;Monika Haemmerle,&nbsp;Tony Gutschner","doi":"10.1002/cac2.12660","DOIUrl":"10.1002/cac2.12660","url":null,"abstract":"&lt;p&gt;Oral squamous cell carcinoma (OSCC), a major subgroup of head and neck squamous cell carcinoma (HNSCC), is an aggressive disease that preferentially spreads to cervical lymph nodes. Positive lymph node status is an important predictor of survival in OSCC [&lt;span&gt;1-3&lt;/span&gt;]. Hence, a better understanding of the molecular mechanisms underlying oral cancer metastasis and the identification of therapeutic vulnerabilities are needed to prevent and treat metastatic disease.&lt;/p&gt;&lt;p&gt;We collected 87 primary tumors and 21 lymph node metastasis (LNM) from 72 OSCC patients to conduct comprehensive transcriptome-wide expression and correlation analyses (Figure 1A). First, we performed expression-based clustering with all primary tumors and observed the best subdivision with &lt;i&gt;k&lt;/i&gt; = 3 using protein-coding and non-coding genes (Figure 1B). Of note, we observed transcriptional heterogeneity among multiregional tumor samples in about 30% of the cases, leading to the assignment of these patients and their respective tumors to different clusters. Intriguingly, Kaplan-Meier analysis of patients whose tumors were unambiguously assigned to only one cluster revealed that cluster 3 (C3) had the worst outcome, with a median survival of 15.6 months compared to 28.57 and 36.53 months for clusters 1 (C1) and 2 (C2), respectively (Figure 1C). Importantly, prognostic factors known to negatively affect survival, such as high T, N, and G status, were not enriched in C3 tumors (Supplementary Figure S1A-C). However, gene expression analysis identified 244 genes that were significantly changed in C3 compared to C1/2 tumors (Supplementary Figure S1D, Supplementary Table S1). Of note, cell cycle-related gene sets, including Early region 2 binding factor (&lt;i&gt;E2F&lt;/i&gt;) and Myelocytomatosis oncogene (&lt;i&gt;MYC&lt;/i&gt;) target genes, along with other oncogenic signaling pathways, showed a positive normalized enrichment score (NES), potentially explaining the poor outcomes of C3 tumors (Supplementary Figure S1E).&lt;/p&gt;&lt;p&gt;Next, we performed a gene expression-based overall survival (OS) analysis and identified two significant genes, namely Zinc Finger Protein 443 (&lt;i&gt;ZNF443&lt;/i&gt;) and Serine Hydroxymethyltransferase 2 (&lt;i&gt;SHMT2&lt;/i&gt;) (Figure 1D, Supplementary Table S2). Specifically, &lt;i&gt;ZNF443&lt;/i&gt; expression was associated with a reduced risk (Hazard ratio [HR] = 0.238), whereas expression of &lt;i&gt;SHMT2&lt;/i&gt; (HR = 4.028) suggested a higher risk of mortality. Thus, we further tested their prognostic relevance for OS and recurrence/disease-free survival (RFS/DFS) in our patient cohort (Figure 1E, Supplementary Figure S2A-C) as well as in The Cancer Genome Atlas (TCGA) HNSCC dataset (Supplementary Figure S2D-E) [&lt;span&gt;4&lt;/span&gt;]. These analyses indicated that &lt;i&gt;SHMT2&lt;/i&gt;, but not &lt;i&gt;ZNF443&lt;/i&gt;, might serve as an OSCC-specific biomarker for OS. In line with this, &lt;i&gt;SHMT2&lt;/i&gt; expression was higher in HNSCC tissues compared to normal tissues, as well as in T4 versus T1 tumors of the OSCC subtype, and its ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"433-437"},"PeriodicalIF":20.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HER2 and HER3 expression during neoadjuvant treatment of HER2-negative early breast cancer: potential for biomarker-driven sequencing of T-DXd and HER3-DXd","authors":"Christian Fridolin Singer,&nbsp;Stephan Wenzel Jahn,&nbsp;Dominik Hlauschek,&nbsp;Ulrike Maria Heber,&nbsp;Charlotte Mang-Manger,&nbsp;Daniel Egle,&nbsp;Marija Balic,&nbsp;Angelika Pichler,&nbsp;Georg Pfeiler,&nbsp;Stephanie Kacerovsky-Strobl,&nbsp;Christoph Suppan,&nbsp;Magdalena Ritter,&nbsp;Edgar Petru,&nbsp;Richard Greil,&nbsp;Zsuzsanna Bago-Horvath,&nbsp;Christine Deutschmann,&nbsp;Günther Georg Steger,&nbsp;Michael Seifert,&nbsp;Florian Fitzal,&nbsp;Rupert Bartsch,&nbsp;Anu Santhanagopal,&nbsp;Jana Machacek-Link,&nbsp;Dalila Sellami,&nbsp;Magdalena Schwarz,&nbsp;Christian Fesl,&nbsp;Lidija Sölkner,&nbsp;Stephen Esker,&nbsp;Martin Filipits,&nbsp;Michael Gnant,&nbsp;the Austrian Breast and Colorectal Cancer Study Group","doi":"10.1002/cac2.12657","DOIUrl":"10.1002/cac2.12657","url":null,"abstract":"&lt;p&gt;With the development of novel antibody-drug conjugates (ADC) such as T-DXd (trastuzumab deruxtecan) and HER3-DXd (patritumab deruxtecan), global tumor cell targeting has become possible beyond the human epidermal growth factor receptor (HER) 2-positive setting [&lt;span&gt;1, 2&lt;/span&gt;]. Both drugs offer promising options for individualized treatment targeting HER2 and HER3 expression, potentially even in tumors which are currently considered “HER2-negative”. Relatively little is known about the efficacy of HER3-DXd in tumors with low HER3 expression, except for data from one recent study investigating its efficacy across different HER3 expression levels [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The DESTINY-Breast04 trial (NCT03734029) demonstrated that T-DXd-treated patients with HER2-low expressing metastatic breast cancer had significantly longer progression-free and overall survival than those who were treated with the physician's choice of chemotherapy [&lt;span&gt;4&lt;/span&gt;]. It is therefore important to understand whether neoadjuvant systemic therapy is able to induce or up-regulate HER2 and/or HER3 protein expression – raising the hope that neoadjuvant chemotherapy (NACT) and neoadjuvant endocrine therapy (NET) could be used to “prime” tumor cells for subsequent HER-targeting by adjuvant systemic therapy in case of non- pathologic complete remission (pCR). Therefore, we investigated the dynamics of HER2 and HER3 expression in HER2 non-amplified breast cancer by retrospectively analyzing the immunohistochemical HER2 and HER3 protein expression in pre- and post-treatment tumor samples, treated with neoadjuvant systemic chemo- and endocrine therapy, from the prospectively randomized ABCSG 34 trial.&lt;/p&gt;&lt;p&gt;The trial design, inclusion criteria, and main clinical results of this trial were reported previously [&lt;span&gt;5&lt;/span&gt;]. Briefly, in ABCSG 34, 400 pre- and post-menopausal women with HER2-negative early breast cancer received either standard-of-care (SoC) NACT (&lt;i&gt;n&lt;/i&gt; = 311) or NET (&lt;i&gt;n&lt;/i&gt; = 98), with or without the Mucin-1 (MUC1) directed vaccine tecemotide (Supplementary Methods). Immunohistochemical data on HER2 and HER3 expression were available from paired pre- and post-treatment samples of 183 of these patients (Supplementary Figure S1), which did not significantly differ from the overall study population regarding clinical-pathological parameters (Supplementary Table S1).&lt;/p&gt;&lt;p&gt;In tumors that had been subjected to SoC NACT, HER2 expression was detected at baseline in 57/134 (42.5%) tumors, with low expression (1+) in 39.6%, and equivocal expression (2+) in 3.0% of cases. HER2 expression in the post-treatment surgical samples was detected in 68/134 (50.7%) tumors, with a HER2 score of 1+ in 43.3%, and a HER2 score of 2+ in 7.5% of tumor samples (&lt;i&gt;p&lt;/i&gt; = 0.050 for marginal homogeneity). This corresponds to an increase of HER2 from baseline to surgery in 34/134 (25.4%; 95% CI, 18.8% to 33.4%) tumors, and a decrease in response to SoC NACT in 19/134 (14.2%; 95","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"428-432"},"PeriodicalIF":20.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A prospective, phase II, neoadjuvant study based on chemotherapy sensitivity in HR+/HER2- breast cancer-FINEST study","authors":"Li Chen,&nbsp;Wen-Ya Wu,&nbsp;Fei Liang,&nbsp;Guang-Yu Liu,&nbsp;Ke-Da Yu,&nbsp;Jiong Wu,&nbsp;Gen-Hong Di,&nbsp;Lei Fan,&nbsp;Zhong-Hua Wang,&nbsp;Jun-Jie Li,&nbsp;Zhi-Ming Shao","doi":"10.1002/cac2.12649","DOIUrl":"10.1002/cac2.12649","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Hormone receptor-positive (HR+)/humaal growth factor receptor 2-negative (HER2-) breast cancer, the most common breast cancer type, has variable prognosis and high recurrence risk. Neoadjuvant therapy is recommended for median-high risk HR+/HER2- patients. This phase II, single-arm, prospective study aimed to explore appropriate neoadjuvant treatment strategies for HR+/HER2- breast cancer patients.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Eligible female patients with newly diagnosed, untreated HR+/HER2- breast cancer received 2 cycles of nab-paclitaxel and carboplatin (nabPCb). Magnetic resonance imaging (MRI) was performed to assess tumor responses, and &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mo&gt;≥&lt;/mo&gt;\u0000 &lt;annotation&gt;$ ge $&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt;40% regression of the maximal tumor diameter was deemed chemo-sensitive. Chemo-sensitive patients continued nabPCb for 4 more cycles (group A). Chemo-insensitive patients were randomized to groups B, C, and D at a ratio of 1:3:1 to receive a new chemotherapy for 4 cycles or endocrine-immune-based therapy (dalpiciclib, letrozole and adebrelimab, with goserelin if patients were premenopausal) for 4 cycles or to undergo surgery. Peripheral blood and core-needle biopsy (CNB) samples were collected before treatment, followed by a next-generation sequencing (NGS) panel detection and similarity network fusion (SNF) typing through digital pathology data. The primary endpoint was the pathological complete response (pCR) rate, and the secondary endpoint was the clinical objective response rate (ORR).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 121 patients were enrolled (67.8% with stage III disease), with 76, 9, 27, and 9 patients in groups A, B, C and D, respectively. The total pCR rate was 4.1%, and all patients who received pCR were in group A. Group C had a better ORR than Group B (81.5% vs. 66.7%). Exploratory analysis revealed that patients with the SNF4 subtype were the most sensitive to nabPCb (pCR rate of 21.1% vs. 1.8% in group A), whereas patients in group C with the SNF2 subtype were more sensitive to endocrine-immune-based therapy (Miller-Payne grade 4-5, 45.5% vs. 6.3%).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Converting to endocrine-immune-based therapy improved the ORR, but not the pCR rate in chemo-insensitive patients. Neoadjuvant chemotherapy and endocrine therapy are not mutually exclusive. The SNF4 subtype of HR+/HER2- breast cancer was m","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"411-421"},"PeriodicalIF":20.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12649","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkin deficiency promotes colorectal tumorigenesis and progression through RIPK3-dependent necroptotic inflammation","authors":"Zheming Wu,&nbsp;Huaping Xiao,&nbsp;Jake A Kloeber,&nbsp;Yaobin Ouyang,&nbsp;Ping Yin,&nbsp;Jinzhou Huang,&nbsp;Bin Chen,&nbsp;Shouhai Zhu,&nbsp;Jing Lu,&nbsp;Yiqun Han,&nbsp;Xinyi Tu,&nbsp;Sonja Dragojevic,&nbsp;Kuntian Luo,&nbsp;Adrian T Ting,&nbsp;Meng Welliver,&nbsp;Zhenkun Lou","doi":"10.1002/cac2.12648","DOIUrl":"10.1002/cac2.12648","url":null,"abstract":"&lt;p&gt;Colorectal cancer (CRC), recognized as one of the most commonly diagnosed cancers globally, is a complex disease influenced by various factors, including lifestyle, genetics, and the environment [&lt;span&gt;1&lt;/span&gt;]. Chronic bowel inflammation is one of the primary contributors to colorectal carcinogenesis [&lt;span&gt;2&lt;/span&gt;]. The persistent systemic inflammatory response associated with tumors contributes to cachexia and malnutrition in patient, leading to increased morbidity and mortality. Previous studies have demonstrated that Parkin acts as a negative regulator of necroptosis by binding to and polyubiquitinating RIPK3 (Receptor-Interacting Protein Kinase 3), a pivotal regulator of necroptosis [&lt;span&gt;3&lt;/span&gt;]. Loss of Parkin promotes hyperactivation of RIPK3, necroptosis, and inflammation-driven colorectal tumorigenesis. In colitis-associated models, inhibiting RIPK3 significantly reduces pro-inflammatory cytokine expression and cancerous polyp formation. However, the role of RIPK3 in tumorigenesis is complex [&lt;span&gt;4, 5&lt;/span&gt;], and the physiological relationship between Parkin and RIPK3 in vivo remains incompletely understood.&lt;/p&gt;&lt;p&gt;To further investigate the tumor-suppressive effect of Parkin through the inhibition of RIPK3 in vivo, we crossed &lt;i&gt;Prkn&lt;/i&gt; &lt;sup&gt;−/−&lt;/sup&gt; mice and &lt;i&gt;Ripk3&lt;/i&gt; &lt;sup&gt;−/−&lt;/sup&gt; mice to generate &lt;i&gt;Prkn&lt;/i&gt;/&lt;i&gt;Ripk3&lt;/i&gt; double-knockout (DKO) mice from heterozygous &lt;i&gt;Prkn&lt;/i&gt; &lt;sup&gt;+/−&lt;/sup&gt; &lt;i&gt;Ripk3&lt;/i&gt; &lt;sup&gt;+/−&lt;/sup&gt; breeding pairs [&lt;span&gt;6, 7&lt;/span&gt;]. The DKO mice were born at the expected Mendelian frequencies and were viable, healthy, and fertile (Figure 1A). Genotyping, genome sequence and Western blot analysis of mice from each group confirmed the successful generation of &lt;i&gt;Prkn&lt;/i&gt; &lt;sup&gt;−/−&lt;/sup&gt;, &lt;i&gt;Ripk3&lt;/i&gt; &lt;sup&gt;−/−&lt;/sup&gt; and DKO (Supplementary Figure S1, Supplementary Table S1). Long-term observations revealed that &lt;i&gt;Prkn&lt;/i&gt; &lt;sup&gt;−/−&lt;/sup&gt; mice had shorter lifespans and began to die around 8 months of age (Figure 1B). In contrast, &lt;i&gt;Ripk3&lt;/i&gt; single-knockout mice and DKO mice exhibited survival curves similar to those of wide-type (WT) mice. These results indicate that Parkin deficiency may induce abnormalities that contribute to reduced survival, and this phenotype is regulated by Ripk3.&lt;/p&gt;&lt;p&gt;As reported previously [&lt;span&gt;3&lt;/span&gt;], we found an increased frequency of rectal prolapse in &lt;i&gt;Prkn &lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice (Figure 1C, Supplementary Figure S2A). However, in DKO mice, the number of mice with rectal prolapse significantly decreased. Meanwhile, the weight of &lt;i&gt;Prkn &lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice was significantly less than that of WT mice (Supplementary Figure S2B). However, further knockout of &lt;i&gt;Ripk3&lt;/i&gt; in &lt;i&gt;Prkn &lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice did not rescue this low-weight phenotype. To explore this further, we dissected mice of all genotypes with similar ages and genders and found that the &lt;i&gt;Prkn &lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice had more polyps and obvious lesion in their small intestine, while knocking o","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"406-410"},"PeriodicalIF":20.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics reveals tumor microenvironment factors underlying poor immunotherapy responses in ALK-positive lung cancer","authors":"Seungbyn Baek,&nbsp;Euijeong Sung,&nbsp;Gamin Kim,&nbsp;Min Hee Hong,&nbsp;Chang Young Lee,&nbsp;Hyo Sup Shim,&nbsp;Seong Yong Park,&nbsp;Hye Ryun Kim,&nbsp;Insuk Lee","doi":"10.1002/cac2.12658","DOIUrl":"10.1002/cac2.12658","url":null,"abstract":"&lt;p&gt;Lung cancer remains the leading cause of cancer death in 2024, with ∼80% being non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) rearrangements occur in ∼5% of NSCLC cases, typically treated with ALK inhibitors, though resistance often develops [&lt;span&gt;1&lt;/span&gt;]. Immunotherapy has been explored for advanced or resistant ALK-positive NSCLC, but immune checkpoint blockade (ICB) treatments have shown limited clinical benefits [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;A comprehensive study of ALK-positive NSCLC tumor microenvironment (TME) is needed to understand immunotherapy limitations and improve treatment strategies. We generated and collected single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase Accessible Chromatin with high-throughput sequencing (scATAC-seq) datasets from lung adenocarcinoma (LUAD) patients with ALK rearrangements and wild type without major oncogenic drivers (WT) (Supplementary Table S1). By comparing TME, we aimed to identify features explaining poor immunotherapy responses (Figure 1A).&lt;/p&gt;&lt;p&gt;After batch corrections for each of the RNA and ATAC profiles, we identified epithelial, stromal, and immune cells (Supplementary Figure S1A, Supplementary Table S2). From the immune compartment, we identified major cell types such as myeloid cells, T cells, natural killer (NK) cells, and B cells (Figure 1B, Supplementary Figure S1B, Supplementary Table S3). Integration of the RNA and ATAC profiles confirmed consistency between these two omics profiles (Supplementary Figure S1C-D). Compositional analysis revealed that ALK-positive samples showed an enrichment of innate immune cells (myeloid and NK cells) and depletion of adaptive immune cells (T and B cells) (Figure 1C, Supplementary Figure S1E-F), suggesting weak adaptive anti-tumoral responses in ALK-positive TME.&lt;/p&gt;&lt;p&gt;Oncogenic mutations primarily impact epithelial cells, so we classified epithelial cell malignancy with the cell-classifier and copy number variations (Supplementary Figure S1G-H) and measured &lt;i&gt;ALK&lt;/i&gt; and &lt;i&gt;PD-L1&lt;/i&gt; expression. Malignant cells expressing &lt;i&gt;ALK&lt;/i&gt; or &lt;i&gt;PD-L1&lt;/i&gt; were predominantly from ALK-positive malignant cells (Supplementary Figure S1I). We observed that ALK-positive tumors had a higher malignant-to-normal epithelial cell ratio than WT tumors (Figure 1D). Additionally, malignant cells in ALK-positive tumors exhibited increased stemness, indicating greater developmental potential (Figure 1E). Top 100 upregulated genes in ALK-positive tumors were linked to aggressive cancer pathways like epithelial-mesenchymal transition (EMT) and hypoxia [&lt;span&gt;2&lt;/span&gt;] (Figure 1F).&lt;/p&gt;&lt;p&gt;To identify malignant subsets with higher progression potential, we constructed developmental trajectories (Supplementary Figure S1J). State 4, enriched with ALK-positive malignant cells, showed higher stemness and elevated stress, hypoxia, and EMT gene signatures (Supplementary Figure S1J-L, Supplementary Table S4). Survival analysis with LUAD pa","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"422-427"},"PeriodicalIF":20.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12658","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence of and survival with bone and soft tissue sarcoma: A nation-wide study over four decades","authors":"Maria Anna Smolle,&nbsp;Florian Alexander Wenzl,&nbsp;Joanna Szkandera,&nbsp;Susanne Scheipl,&nbsp;Bernadette Liegl-Atzwanger,&nbsp;Jasminka Igrec,&nbsp;Andreas Leithner","doi":"10.1002/cac2.12653","DOIUrl":"10.1002/cac2.12653","url":null,"abstract":"&lt;p&gt;Demographic and environmental factors determine the incidence of and survival with malignancies, including sarcoma [&lt;span&gt;1&lt;/span&gt;]. Accordingly, the annual incidence of soft tissue sarcomas (STS) has markedly increased since the early 2000s [&lt;span&gt;2, 3&lt;/span&gt;]. Likewise, there appears to be an overall increase in the incidence of bone sarcomas (BS) since 1975 [&lt;span&gt;4, 5&lt;/span&gt;]. In parallel, one study reports moderate improvement in the survival of adult patients with BS and STS up to 2007 [&lt;span&gt;6&lt;/span&gt;]. Previous studies were often based on cancer registries with low coverage rates [&lt;span&gt;3, 7, 8&lt;/span&gt;], focused on limited time periods [&lt;span&gt;3, 9, 10&lt;/span&gt;], or did not include data from recent years [&lt;span&gt;3, 6&lt;/span&gt;]. Thus, current data from high-income European countries with an advanced health care system on incidence and prognosis of sarcoma patients are scarce. Consequently, the purpose of this study was to analyse the incidence of and survival with BS and STS in the general population of Austria from 1983 to 2020. A detailed description of materials and methods is outlined in the Supplementary Materials (Supplementary Materials and Methods).&lt;/p&gt;&lt;p&gt;Across the 38-year observation period, 2,491 patients in Austria were diagnosed with BS (Supplementary Tables S1-S2, Supplementary Figure S1). Male-to-female ratio was 1.27, favouring males (range over the years: 0.56-1.23), which remained constant over time &lt;i&gt;(P =&lt;/i&gt; 0.529; Supplementary Table S3).&lt;/p&gt;&lt;p&gt;Throughout the observation period, mean age-adjusted BS incidence was 0.80 per 100,000 (95% confidence interval [CI]: 0.61-0.98; Figure 1A). We observed a significant increase in incidence from 1983 to 2020, with an average annual percentage change (AAPC) of 7.2% (95%CI: 6.2%-8.5%; &lt;i&gt;P&lt;/i&gt; &lt; 0.001; Supplementary Table S4). Similar results were obtained in a sensitivity analysis excluding the initial 7 years of the observation period (&lt;i&gt;ie&lt;/i&gt;, 1983-1989; AAPC: 1.5% [95%CI: 1.0%-2.1%]; &lt;i&gt;P&lt;/i&gt; &lt; 0.001) and chondrosarcoma diagnoses (AAPC: 5.8% [95%CI: 4.9%-7.2%]; &lt;i&gt;P&lt;/i&gt; &lt; 0.001; Supplementary Figure S2A; Supplementary Table S4).&lt;/p&gt;&lt;p&gt;Age at diagnosis of BS followed a bimodal distribution, with peaks in incidence around the age of 15 years and 70 years (Figure 1B), both in males and females (Supplementary Figure S3A). Notably, a shift towards increased BS incidence in older age groups was present in recent years (Supplementary Figure S4A, Supplementary Figure S5A). In a sensitivity analysis excluding all chondrosarcoma diagnoses, a similar pattern was observed (Supplementary Figure S2B).&lt;/p&gt;&lt;p&gt;Five-year relative survival was 65.9% (95%CI: 63.9%-67.9%). No change in 5-year relative survival was found from the first time period (1987-1990; 5-year relative survival: 65.3% [95%CI: 50.7%-76.7%]) to the last time period (2015-2020; 5-year relative survival: 66.7% [95%CI: 62.5%70.7%]; &lt;i&gt;P&lt;/i&gt; = 0.735; Figure 1C). Of note, the youngest age group (0-20 years) had better 5-year r","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"397-400"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic and regulatory T cell interactions calculated from image mass cytometry predict immunochemotherapy response in triple-negative breast cancer","authors":"Xiang Wang,&nbsp;Jing Dong,&nbsp;Jian-Rong Li,&nbsp;Yupei Lin,&nbsp;Bikram Sahoo,&nbsp;Yong Li,&nbsp;Yanhong Liu,&nbsp;Robert Taylor Ripley,&nbsp;Jia Wu,&nbsp;Jianjun Zhang,&nbsp;Christopher I Amos,&nbsp;Chao Cheng","doi":"10.1002/cac2.12652","DOIUrl":"10.1002/cac2.12652","url":null,"abstract":"&lt;p&gt;In the tumor microenvironment (TME), various types of immune cells interact with each other and with cancer cells, playing critical roles in cancer progression and treatment [&lt;span&gt;1&lt;/span&gt;]. Numerous studies have reported that the infiltration levels of specific immune cells are associated with patient prognosis and response to immunotherapies [&lt;span&gt;2, 3&lt;/span&gt;]. For instance, the density of pre-existing tumor infiltrating lymphocytes in the TME has been found to positively correlate with patient responses to anti-PD-1 treatment in triple-negative breast cancer (TNBC) [&lt;span&gt;3&lt;/span&gt;]. However, the relationship between immune cell-cell interactions (CCIs) in the TME and patient clinical outcomes remains unclear due to the limited availability of large-scale datasets for systematic CCI investigation. Recently, imaging mass cytometry (IMC) has been utilized to characterize the immune landscape within the TME of tumor samples [&lt;span&gt;4&lt;/span&gt;]. IMC can detect 30 to 40 protein markers on a single tissue slide, enabling the visualization of spatial distributions of various cell types at single-cell resolution. Analyzing IMC data enables the quantification of interactions between all TME cell types by examining their spatial distributions.&lt;/p&gt;&lt;p&gt;In this study, we conducted a systematic analysis to investigate the association between CCIs and treatment responses of cancer patients using a large IMC dataset. The dataset comprises the immune landscape of 660 tumor samples from 279 TNBC patients enrolled in a randomized clinical trial [&lt;span&gt;4&lt;/span&gt;]. These patients were treated with either neoadjuvant chemotherapy (&lt;i&gt;n&lt;/i&gt; = 141) or immunochemotherapy therapy (chemotherapy combined with anti-PD-L1 immunotherapy, (&lt;i&gt;n&lt;/i&gt; = 138), with tumor samples collected at three time points for IMC analysis: baseline, early on-treatment, and post-treatment. We applied a modified method introduced by Windhager &lt;i&gt;et al.&lt;/i&gt; [&lt;span&gt;5&lt;/span&gt;] to quantify interactions for all pairs of cell types captured by IMC and examined their associations with patient outcomes (Supplementary Material and Methods). Our results indicated that compared to the infiltration levels of immune cells, CCIs between specific immune cell types were more strongly correlated with patient responses. Notably, we found that the interaction between regulatory T cells (Treg) and GZMB&lt;sup&gt;+&lt;/sup&gt; cytotoxic CD8&lt;sup&gt;+&lt;/sup&gt; T (Tc) cells in pre-treatment samples was predictive of patient response to immunochemotherapy but not to chemotherapy alone in TNBC.&lt;/p&gt;&lt;p&gt;The processed IMC data provides the coordinates of all single cells along with their cell type annotations. To quantify the interaction from cell type X to Y (X→Y), we calculated the average number of X cells among the 10 nearest neighbors of each Y cell and standardized this as a Z-score by comparing it with a null distribution generated through permutations. In each permutation, we shuffled the labels of all cell types except epithelial cel","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"392-396"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12652","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient 5-ALA-photodynamic therapy in nasopharyngeal carcinoma induces an immunoactivation mediated by tumoral extracellular vesicles and associated with immunogenic cell death","authors":"Camille Trioën,&nbsp;Thomas Soulier,&nbsp;Jacquie Massoud,&nbsp;Clément Bouchez,&nbsp;Nicolas Stoup,&nbsp;Anthony Lefebvre,&nbsp;Anne-Sophie Dewalle,&nbsp;Guillaume Paul Grolez,&nbsp;Nadira Delhem,&nbsp;Olivier Moralès","doi":"10.1002/cac2.12656","DOIUrl":"10.1002/cac2.12656","url":null,"abstract":"&lt;p&gt;Nasopharyngeal carcinoma (NPC) is a rare cancer, with 120,334 cases worldwide in 2022, but it remains endemic in Southeast Asia and North Africa. Early-stage NPC is typically treated with radiotherapy, often combined with chemotherapy for advanced stages [&lt;span&gt;1&lt;/span&gt;]. Despite a 5-year survival rate of 70% to 90% for locoregional disease, late-stage diagnosis and locoregional or distant recurrence and metastasis (R/M) result in a poor prognosis for many patients, underscoring the urgent need for novel therapeutic strategies [&lt;span&gt;2-4&lt;/span&gt;]. The tumor microenvironment, enriched with immunosuppressive elements such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), plays a central role in promoting immune evasion and resistance to therapy. In NPC, effective therapeutic strategies should not only induce tumor cell death but also reprogram this immunosuppressive microenvironment to restore robust anti-tumor immunity. To address these challenges, we propose evaluating the efficacy of photodynamic therapy (PDT) and its immunoactivating properties in NPC. PDT is a non-invasive treatment that induces cell death via reactive oxygen species (ROS) and activates an anti-tumor immune response by releasing tumor antigens and damage-associated molecular patterns (DAMPs) [&lt;span&gt;5, 6&lt;/span&gt;]. After examining the direct cell death induced by 5-aminolevulinic acid (5-ALA)-PDT, we investigated its ability to trigger immune activation and its effects on immune cell populations and their secretome. Lastly, we conducted an in-depth analysis of molecular and vesicular (extracellular vesicle) components to understand the mechanisms underlying immune response activation. Detailed study designs and methods are available in the Supplementary Materials.&lt;/p&gt;&lt;p&gt;The prodrug 5-ALA is preferentially absorbed by tumor cells and metabolized into protoporphyrin IX (PpIX), the photosensitizer, via the heme synthesis pathway (Supplementary Figure S1A). To evaluate 5-ALA-PDT in NPC cell lines, we assessed their capacity to convert 5-ALA into PpIX. We observed that NPC cell lines expressed key enzymes and transporters involved in the heme pathway, with no significant differences, confirming their ability to metabolize 5-ALA into PpIX (Supplementary Figure S1B). We then incubated NPC cells with varying concentrations of 5-ALA, showing successful conversion of 5-ALA into intracellular PpIX after 2 hours, followed by extracellular release of PpIX between 6 to 8 hours (Figure 1A, Supplementary Figure S1C). Based on these findings and considering clinical data, we selected a 4-hour incubation period for subsequent experiments.&lt;/p&gt;&lt;p&gt;To determine the direct impact and efficacy of 5-ALA-PDT on NPC cell lines, we subjected the cells to 5-ALA-PDT. A dose-dependent reduction in cell viability was observed, with CNE2 cells (EC50: 104.9 µmol/L) exhibiting greater sensitivity to treatment compared to CNE1 cells (EC50: 209.7 µmol/L) (Figure 1B, Suppl","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"401-405"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12656","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiscale 3D spatial analysis of the tumor microenvironment using whole-tissue digital histopathology","authors":"Daniel Shafiee Kermany,&nbsp;Ju Young Ahn,&nbsp;Matthew Vasquez,&nbsp;Weijie Zhang,&nbsp;Lin Wang,&nbsp;Kai Liu,&nbsp;Zhan Xu,&nbsp;Min Soon Cho,&nbsp;Wendolyn Carlos-Alcalde,&nbsp;Hani Lee,&nbsp;Raksha Raghunathan,&nbsp;Jianting Sheng,&nbsp;Xiaoxin Hao,&nbsp;Hong Zhao,&nbsp;Vahid Afshar-Kharghan,&nbsp;Xiang Hong-Fei Zhang,&nbsp;Stephen Tin Chi Wong","doi":"10.1002/cac2.12655","DOIUrl":"10.1002/cac2.12655","url":null,"abstract":"&lt;p&gt;Spatial statistics are crucial for analyzing clustering patterns in various spaces, such as the distribution of trees in a forest or stars in the sky. Advances in spatial biology, such as single-cell spatial transcriptomics, enable researchers to map gene expression patterns within tissues, offering unprecedented insights into cellular functions and disease pathology. Common methods for deriving spatial relationships include density-based methods (quadrat analysis, kernel density estimators) and distance-based methods (nearest-neighbor distance [NND], Ripley's K function). While density-based methods are effective for visualization, they struggle with quantification due to sensitivity to parameters and complex significance tests. In contrast, distance-based methods offer robust frameworks for hypothesis testing, quantifying spatial clustering or dispersion, and facilitating comparisons with models such as uniform random distributions or Poisson processes [&lt;span&gt;1, 2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Ripley's K function provides a detailed measure of spatial clustering or dispersion across multiple scales by considering all pairs of points within specified distances. This is in contrast to NND, which may overlook structures that vary across scales. Ripley's K function can detect complex spatial patterns over a range of distances, making it suitable for datasets with non-uniform arrangements that exhibit different behaviors at different scales. However, its broader adoption has been hindered by computational complexity and challenges in interpretation, especially for three-dimensional data, which are common in spatial biomedical research [&lt;span&gt;3-6&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To address these limitations, we introduce MDSpacer (Multi-Dimensional Spatial Pattern Analysis with Comparable and Extendable Ripley's K), a modeling tool that implements Ripley's K function for both 2D and 3D data, facilitating detailed analyses within and between groups (Figure 1A, B, Supplementary Figure S1). MDSpacer uses a novel normalization scheme (described in Supplementary Materials and Methods) that dramatically reduces computational overhead while delivering results in an easily interpretable and comparable format (Figure 1C–F). We validated this tool in two cancer research studies: one on metastatic bone cancer and another on ovarian cancer. In the metastatic bone cancer study, we used the Vessel3D analysis toolkit to extract spatial point information from 3D confocal images of murine femurs with early-stage spontaneous metastasis (Figure 1G–K, Supplementary Figures S2, S3, Supplementary Videos S1, S2). MDSpacer identified both expected clustering at short distances and unexpected dispersion patterns at larger scales between early-stage disseminated tumor cells (DTCs) and neural/glial antigen 2-positive (NG2&lt;sup&gt;+&lt;/sup&gt;) mesenchymal cells in relation to other microenvironmental factors [&lt;span&gt;7-9&lt;/span&gt;]. Interestingly, no spatial relationships were observed between DTCs and vessel bifurcatio","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"386-390"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12655","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}