Cancer Communications最新文献

{"title":"Wnt/GSK-3β mediates posttranslational modifications of FLYWCH1 to regulate intestinal epithelial function and tumorigenesis in the colon","authors":"Sheema Almozyan, Roya Babaei-Jadidi, Abrar Aljohani, Sepideh Youssefi, William Dalleywater, Prerna Kadam, Bradley Spencer-Dene, Emad Rakha, Mohammad Ilyas, Abdolrahman Shams Nateri","doi":"10.1002/cac2.12625","DOIUrl":"10.1002/cac2.12625","url":null,"abstract":"<p>The intestinal epithelium undergoes rapid renewal, with the entire epithelial layer replaced within five days. Intestinal stem cells (ISCs), located in the intestinal crypts, generate all differentiated cell types necessary for intestinal function. Key signalling pathways involved in stem cell maintenance include Wnt, Notch, Hedgehog, and BMP. Wnt signalling, primarily driven by crypt cells, creates a signalling gradient to maintain homeostasis [<span>1</span>]. However, nuclear β-catenin, the key regulator of Wnt signalling, correlates positively with tumorigenesis. While crypt base cells also exhibit high levels of nuclear β-catenin, the regulatory mechanism in normal tissue versus tumor remains unclear [<span>1</span>]. FLYWCH-Type Zinc Finger 1 (FLYWCH1), an uncharacterised transcription factor, binds unphosphorylated-β-catenin [<span>2</span>], is associated with H3K9me3 in (peri)centromeric chromatin [<span>3</span>], and colocalizes with γ-H2AX foci [<span>4</span>]. While its deletion is embryonically lethal in mice [<span>5</span>], the specific role and regulation of FLYWCH1 in tissue homeostasis and tumorigenesis remain unclear.</p><p>This study investigates the role of FLYWCH1 in intestinal stem cell regulation and its impact on colorectal cancer. We hypothesize that FLYWCH1 directly influences ISC function by modulating critical signalling pathways, thereby playing a significant role in the initiation and progression of colorectal cancer (CRC).</p><p>To assess the significance of FLYWCH1 expression in intestinal tissue homeostasis, we first examined its expression in murine tissues. Data from BioGPS (http://biogps.org) and the mouse gene expression database indicate varying tissue expression of <i>Flywch1</i>, with the highest level observed in the brain (Supplementary Figure S1). To confirm this, we conducted in-situ hybridisation (ISH) analysis to identify distinct cell type-specific expression patterns in the brain and intestinal tissues. ISH was performed using a Digoxigenin-labelled antisense-RNA probe for <i>Flywch1</i> mRNA on representative brain, liver and intestinal sections from 16-week-old wild-type mice (Supplementary Figure S2A-G). We observed high expression of <i>Flywch1</i> in cells located alongside the ISC marker Olfactomedin-4 (<i>Olmf4</i>)-positive cells, while <i>Flywch1</i> was not detectable in the differentiated epithelial cells of the intestinal villi (Supplementary Figure S2D-E). In addition, we examined the differential expression of FLYWCH1 during carcinogenesis, initially in the intestine of <i>Apc</i><sup>Min+/−</sup> mice, which harbour tumors and adjacent non-tumor regions. <i>Flywch1</i> expression was substantially downregulated in intestinal neoplastic crypts compared to normal crypts (Supplementary Figure S2F-G). This is consistent with FLYWCH1 expression in human CRC tissues (Figure 1A-B, Supplementary Table S1). Collectively, these studies suggest a potential role for FLYWCH1 in ISC and the ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"9-14"},"PeriodicalIF":20.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543910","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":"Engineering heavy chain antibody-drug conjugates against solid tumors for a one-shot kill","authors":"Xue Liu, Wenjing Ning, Lei Wang, Han Liu, Hongye Zeng, Xiaojing Qin, Yuanzhi Chen, Fentian Chen, Lin Xu, Yang Zhao, Xiaoqing Chen, Jixian Tang, Yunlong Ren, Xiaowen Yan, Wenxin Luo, Ningshao Xia","doi":"10.1002/cac2.12616","DOIUrl":"10.1002/cac2.12616","url":null,"abstract":"<p>The inefficient tumor penetration of conventional antibodies has hampered the effective use of antibody-drug conjugates (ADCs) against solid tumors [<span>1-5</span>]. Compared with full-length antibodies and single-chain variable fragment (scFv), nanobodies (Nbs) have much smaller molecular weights, allowing them to achieve deeper tissue penetration, and they have become an attractive candidate platform for conjugating small-molecule drugs and tracers because of their favourable thermostability and high bioengineering potential [<span>6, 7</span>]. However, the clinical application of Nb-based ADCs is limited due to the short half-life of the Nbs [<span>8</span>]. This letter reports the identification and biological characterization of an innovative heavy chain antibody (HCAb)-drug conjugate based on a Nb from a trophoblast cell surface antigen 2 (TROP2)-immunized alpaca. HCAb has been verified to possess fast and efficient penetration into tumor tissues as its molecular weight (∼80 kDa) is half that of a classical antibody (∼150 kDa) [<span>9</span>]. We mutated the sites serine 149 and lysine 200 of the HCAb to cysteine, and then coupled the antimitotic agent monomethyl auristatin E (MMAE) to the engineered surface cysteine with the proteolyzable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-Val-Cit-PAB), resulting in a conjugate abbreviated as C3 ADC (Figure 1A). Compared with conventional RS7 ADC, C3 ADC exhibits exceptionally higher stability, much deeper tumor penetration, significantly greater tumor uptake, and faster accumulation at tumor sites, leading to improved tumor inhibition. Notably, the engineered Nb-drug conjugate exhibits potent ‘one-shot kill’ efficacy against solid tumors. This study presents, for the first time, a HCAb drug conjugate strategy that can efficiently reduce tumor burden.</p><p>We screened and identified the TROP2 Nb following our protocol for specific Nbs (Supplementary Figure S1). To enhance the expression and extend the half-life, the Nb was fused with an hFc domain, termed C1 HCAb. C1 HCAb-DyLight 633 was more significantly endocytosed by TROP2-overexpressing MDA-MB-231 cells in a time-dependent manner than RS7-DyLight 633 (Figure 1B and Supplementary Figure S2). In contrast, Huh7 cells without TROP2 expression had poor internalization of C1 HCAb (Supplementary Figure S3). These results indicated that C1 HCAb can be selectively taken up by tumor cells expressing high levels of TROP2.</p><p>We then performed site-directed mutagenesis to design a site-specific mutant antibody, C3 HCAb (Supplementary Figures S4-S5). Here, lysosomal-cleavable MC-Val-Cit-PAB was used as a linker and the antimitotic agent MMAE was coupled to the engineered surface of cysteine, forming the conjugate C3 ADC. For the positive ADC control, site-directed mutation of the antibody portion of the FDA-approved ADC Trodelvy (sacituzumab) (hRS7) was performed at the same site, and the antibody was conjugated wit","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1444-1448"},"PeriodicalIF":20.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495686","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":"HLX07 alone or combined with serplulimab, cisplatin and 5-fluorouracil for advanced esophageal squamous cell carcinoma: A phase 2 study","authors":"Yun Liu, Yanfeng Wang, Yanrong Zhu, Tao Wu, Zhenyang Liu, Jin Zhou, Yuan Yuan, Mudan Yang, Bo Liu, Zhenbo Tan, Wu Zhuang, Jiayan Chen, Ning Li, Ying Wang, Xuhui Hu, Lin Wang, Haoyu Yu, Qingyu Wang, Jun Zhu, Jing Huang","doi":"10.1002/cac2.12621","DOIUrl":"10.1002/cac2.12621","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later-line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This open-label, non-randomized, two-cohort, phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m<sup>2</sup>, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m<sup>2</sup>, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3-4 treatment-related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3-4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab-related pneumonitis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1431-1443"},"PeriodicalIF":20.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495687","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":"Acquired RD3 loss regulates immune surveillance in high-risk and therapy defying progressive neuroblastoma","authors":"Poorvi Subramanian, Sreenidhi Mohanvelu, Dinesh Babu Somasundaram, Sheeja Aravindan, Natarajan Aravindan","doi":"10.1002/cac2.12620","DOIUrl":"10.1002/cac2.12620","url":null,"abstract":"<p>Neuroblastoma (NB) is the most common extra cranial solid tumor in children and comprises one tenth of all childhood cancer deaths. More than half of infants presented with NB, a designated “cold tumor” with low immune cell repertoire in the tumor microenvironment (TME) [<span>1</span>], develop progressive disease (PD). The low numbers of tumor infiltrating lymphocytes (TILs) and the limited anti-tumorigenic potential; low expression of major histocompatibility complex (MHC) class I molecules; limitations in the tumor suppressive immune cell infiltration in TME; and the presence of immune-suppressive cytokines are the critical reasons for poor prognosis (< 10% long term overall survival [OS]) in high-risk NB that contributes to about 10% of all childhood cancer deaths [<span>2</span>]. Immune cell components of both the innate and adaptive immune response recognize tumor specific antigens expressed on neoplastic cells and promote an immune response to eliminate cancer cells and to develop immune memory to prevent recurrence [<span>2, 3</span>]. However, these protective responses can take an impromptu turn in favor of tumor progression in immune-compromised individuals, and those tumors with lower immunogenicity [<span>4</span>]. This establishes cancer immune editing within the TME leading to acquired tumor immune evasion (TIME) that substantially contributes to cancer evolution and poor outcomes [<span>2, 4, 5</span>]. Hence, it is of great interest to unearth the drivers and the mechanisms that coordinate TIME, so as to develop effective therapeutic strategies for high-risk and for therapy defying progressive tumors. Our recent studies sequentially identified the availability and abundance of Retinal Degeneration protein 3 (RD3) in human adult and fetal tissues beyond retina [<span>6, 7</span>]; de novo loss of RD3 expression under therapy pressure; its predictive/prognostic relevance to NB clinical outcomes and; defined its novel NB evolution stabilization function [<span>8, 9</span>]. Assessing the function of RD3 in NB TIME (Figure 1), here we recognized the unique requirement for RD3 to maintain NB immune surveillance.</p><p>The immune microenvironment enclosed within the TME plays a discrete role in tumor immune surveillance. CIBERSORTx analysis (<i>P</i> < 0.05) employing “gene surrogate strategy” in whole genome RNA sequencing (RNA-seq) profiles from our bed-to-bench study identified 22 immune cell-types in NB-TME (Supplementary Figure S1). Differential gene expression analysis within CIBERSORTx [<span>10</span>] in RD3 reverse engineered (RD3-knockout) three unique models inflicted a “model-dependent” loss (vs. RD3<sup>+</sup>) of naïve B cells, CD8-cells, naïve and memory resting CD4-T cells, follicular as well γδ T-cells, resting and activated natural killer (NK) cells, M<sub>0</sub>, M<sub>1</sub>, and M<sub>2</sub> macrophages, resting and activated mast cells, eosinophils and, a “model-independent” loss (vs. RD3<sup>+</s","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1427-1430"},"PeriodicalIF":20.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495685","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":"IL2-mediated modulation of small extracellular vesicles secretion and PD-L1 expression: a novel perspective for neutralizing immune suppression within cancer cells","authors":"Soojeong Noh, Suyeon Ryu, Dokyung Jung, Sanghee Shin, Inseong Jung, Sung-Min Kang, Christine Seulki Kim, Sung-Jin Choi, Hanchae Cho, Melanie Schwämmle, Youngtae Jeong, Felicitas Bucher, Il-Kyu Choi, Shin Yup Lee, Sin-Hyeog Im, Kyungmoo Yea, Moon-Chang Baek","doi":"10.1002/cac2.12623","DOIUrl":"10.1002/cac2.12623","url":null,"abstract":"<p>Cancer cells secrete small extracellular vesicles (sEVs) to regulate various cellular functions, like tumor growth and metastasis, by promoting epithelial-mesenchymal transition and angiogenesis [<span>1, 2</span>]. Additionally, cancer cells evade immune surveillance by upregulating the surface expression of cellular programmed death-ligand 1 (cPD-L1), which interacts with programmed cell death-1 (PD-1) on cytotoxic T cells, suppressing immune responses [<span>3</span>]. Moreover, cancer cells release sEVs displaying PD-L1 on their surface [<span>4</span>]. Cancer-derived exosomal PD-L1 (ePD-L1), similar to cPD-L1 in cancer cells, can hinder immune cell activation, inducing an immunosuppressive tumor microenvironment [<span>5</span>]. Therefore, modulating sEV secretion or PD-L1 expression in cancer cells may be a crucial strategy for altering the tumor microenvironment.</p><p>Herein, we conducted a screening to identify natural factors regulating sEV secretion from cancer cells and discovered that Interleukin-2 (IL2) predominantly reduces sEV secretion in B16F10 cells (Supplementary Figure S1). IL2, a commonly used FDA-approved therapy for melanoma, typically exerts anticancer effects by activating immune cells expressing the IL2 receptor complex (IL2R), consisting of IL2RA, IL2RB, and IL2RG [<span>6-8</span>]. Remarkably, IL2R is also expressed in certain types of cancer cells, including melanoma cells. However, the potential impact of IL2 on IL2R-expressing cancer cells has not been thoroughly investigated.</p><p>To explore the effects of IL2 on cancer cells, we utilized mouse and human melanoma cells expressing IL2R (Supplementary Figure S2A). We treated these melanoma cells with IL2 and subsequently isolated sEVs to assess the impact of IL2 on sEV secretion (Supplementary Figure S2B-D). IL2 reduced the number of secreted sEVs compared to the PBS control (Figure 1A) and significantly decreased the expression of Rab GTPases, which regulate sEV biogenesis and secretion in melanoma cells (Figure 1B and Supplementary Figure S2E). This effect presents a different pattern from the previously known effects of IL2 on sEV regulation in immune cells [<span>9</span>].</p><p>In addition to examining the effects of IL2 on cancer cell-secreted sEVs, we also investigated its impact on immune checkpoints, which are crucial regulators of immune surveillance [<span>5</span>]. Interestingly, IL2 treatment significantly reduced cPD-L1 levels among immune checkpoints in melanoma cells without affecting cell proliferation (Figure 1C and Supplementary Figure S3). IL2 treatment significantly reduced ePD-L1 expression in melanoma cell-derived sEVs, with equal sEV amounts confirmed by sEV markers (Figure 1D and Supplementary Figure S4A-B). Next, we assessed whether regulation of ePD-L1 by IL2 affects CD8<sup>+</sup> T cell activity. sEVs from PBS-treated B16F10 cells significantly reduced Granzyme B levels in CD8<sup>+</sup> T cells compared to control, whereas sE","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1422-1426"},"PeriodicalIF":20.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495688","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":"The long-term spatiotemporal trends in lung cancer burden and its risk factors at global, regional, and national levels, 1992-2021: The Global Burden of Disease Study 2021","authors":"Zegui Tu, Shuangsi Liao, Caini Chen, Caili Li, Qipeng Hu, Chengzhi Cai, Yang Yu, Jieyan Luo, Meijuan Huang","doi":"10.1002/cac2.12622","DOIUrl":"10.1002/cac2.12622","url":null,"abstract":"<p>Lung cancer is among the most common types of malignant tumors and continues to be the primary cause of cancer-related death [<span>1</span>]. Despite many striking advances in disease understanding and novel treatment opinions that have occurred in recent years, the survival of lung cancer continues to be low, which causes an important public health and socioeconomic issue [<span>2</span>]. Previous studies have reported estimates of lung cancer burden before 2019 [<span>3, 4</span>]. However, the latest information on lung cancer including data during the COVID-19 pandemic is lacking. It is important to regularly measure the current trends in lung cancer incidence rate, mortality rate, disability-adjusted life-years (DALYs) rate, and risk factors. This information is crucial for updating health policies to adapt to the fast-changing global health landscape during the COVID-19 pandemic.</p><p>To address the above issues, we utilized the latest Global Burden of Diseases (GBD) 2021 data to update statistics on lung cancer incidence, mortality, and DALYs at global, regional, and national levels during 1992-2021 (Supplementary Materials and Methods) [<span>5</span>]. On a global scale, there was a 75.60% increase in the estimated number of lung cancer incident cases, a 60.15% increase in death cases, and a 49.88% increase in DALYs from 1992 to 2021 (Supplementary Table S1). However, the corresponding age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) had decreased trends (Supplementary Table S2). We found that the trend was not consistent worldwide. The region with a high-middle socio-demographic index (SDI) had the highest number of lung cancer incident cases, death cases, and DALYs in 2021 (Supplementary Table S1). Only the low-middle SDI region experienced an increasing trend in age-standardized rates (ASRs) from 1992 to 2021 (Supplementary Table S2). Whereas, the highest ASIR, ASMR, and ASDR of lung cancer were in the middle-SDI region (Supplementary Table S1). At the country level, compared with 1992, most countries presented a slight downward trend in ASIR, ASMR, and ASDR in 2021. China ranked first in the incidence of lung cancer cases, followed by the United States of America and Japan in 2021 (Figure 1A, Supplementary Table S3). China, the United States of America, and India ranked in the top 3 in death cases and DALYs in 2021 (Figure 1B-C, Supplementary Tables S4 and S5). Monaco, Greenland, and Montenegro reported the highest ASIR, ASMR, and ASDR in 2021 (Figure 1D-F, Supplementary Tables S3-S5). However, Egypt had the largest increase in ASIR, ASMR, and ASDR from 1992 to 2021, followed by Lesotho and Cabo Verde (Figure 1G-I, Supplementary Tables S3-S5). Additionally, in 2021, the rates of lung cancer incidence, mortality, and DALYs in males were 2.23, 2.36, and 2.31 times higher than those in females (Supplementary Figure S1). The ASIR, ASMR, and ASDR of lung cancer in","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1418-1421"},"PeriodicalIF":20.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458712","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":"Nine-fold variation of risk of advanced colorectal neoplasms according to smoking and polygenic risk score: Results from a cross-sectional study in a large screening colonoscopy cohort","authors":"Ruojin Fu, Xuechen Chen, Tobias Niedermaier, Teresa Seum, Michael Hoffmeister, Hermann Brenner","doi":"10.1002/cac2.12618","DOIUrl":"10.1002/cac2.12618","url":null,"abstract":"<p>Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death globally [<span>1</span>]. The slow progression through the adenoma-carcinoma sequence provides great opportunities for prevention by lifestyle intervention and screening [<span>2</span>]. Smoking has been demonstrated to be associated with an increased risk of CRC and an even much stronger increased risk of CRC precursors in a dose-response manner [<span>3, 4</span>]. Gene-environment interaction studies might help unravel the underlying complex mechanisms through which lifestyle risk factors induce colorectal carcinogenesis, and they may disclose the potential for targeted prevention [<span>5</span>]. Although evidence on interactions between smoking and specific single CRC susceptibility locus on the risk of CRC or its precursors is limited [<span>6, 7</span>], polygenic risk score (PRS), aggregating information from a set of CRC-related risk variants identified in genome-wide association studies (GWASs), may help to increase statistical power in gene-environment interaction studies in which interactions may often be missed due to the weak main effects of individual loci and the harsh penalty of multiple comparisons [<span>5</span>]. PRSs have been shown to enhance CRC risk stratification models that already included established lifestyle risk factors of CRC [<span>8, 9</span>]. PRSs also have been shown to be associated with the prevalence of CRC precursors [<span>10</span>]. However, how and to what extent the impact of smoking on the risk of colorectal neoplasms differs by PRS levels is undetermined. We aimed to evaluate the independent and joint impact of smoking and PRS on the risk of colorectal neoplasms in a large colonoscopy screening study. Furthermore, we employed the recently developed “genetic risk equivalent (GRE)” metric [<span>9</span>] to quantify the effect of smoking in terms of equivalent differences in background genetic risk.</p><p>Data for this analysis was drawn from the Begleitende Evaluierung innovativer Testverfahren zur Darmkrebsfrüherkennung (BliTz) study (Supplementary Methods). Participants were classified according to the most advanced finding at colonoscopy as follows: any neoplasm (including advanced neoplasm and non-advanced adenoma) and no finding. Smoking status was classified as never, former, and current smoking. Pack-years of smoking were calculated as a measure of lifetime exposure from the average daily cigarette consumption divided by 20 and multiplied by the duration of smoking in years. The PRS, based on 140 CRC-related single nucleotide polymorphisms (SNPs) identified in a recent large international GWAS [<span>10</span>], was calculated as the weighted sum of the number of risk alleles of the respective variants (Supplementary Table S1). PRS was categorized according to the distribution of PRS by quartiles among participants without colorectal neoplasms.</p><p>Using logistic regressio","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1414-1417"},"PeriodicalIF":20.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458710","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":"Targeting the LMP1-ALIX axis in EBV+ nasopharyngeal carcinoma inhibits immunosuppressive small extracellular vesicle secretion and boosts anti-tumor immunity","authors":"Fajian He, Yan Gong, Gan Tao, Jianguo Zhang, Qiuji Wu, Yushuang Tan, Yajie Cheng, Chunsheng Wang, Jinru Yang, Linzhi Han, Zhihao Wang, Yanping Gao, Jingyi He, Rui Bai, Peikai Sun, Xiaoyan Yu, Yajuan Zhou, Conghua Xie","doi":"10.1002/cac2.12619","DOIUrl":"10.1002/cac2.12619","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immunotherapy has revolutionized the therapeutical regimen for nasopharyngeal carcinoma (NPC), yet its response rate remains insufficient. Programmed death-ligand 1 (PD-L1) on small extracellular vesicles (sEVs) mediates local and peripheral immunosuppression in tumors, and the mechanism of PD-L1 loading into these vesicles is garnering increasing attention. Latent membrane protein 1 (LMP1), a key viral oncoprotein expressed in Epstein-Barr virus (EBV)-positive NPC, contributes to remodeling the tumor microenvironment. However, the precise mechanisms by which LMP1 modulates tumor immunity in NPC remain unclear. Here, we aimed to investigate the roles and regulatory mechanisms of LMP1 and sEV PD-L1 in NPC immune evasion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed the impact of LMP1 on tumor-infiltrating lymphocyte abundance in NPC tissues and humanized tumor-bearing mouse models using multiplex immunofluorescence (mIF) and flow cytometry, respectively. Transmission electron microscopy and nanoparticle tracking analysis were employed to characterize sEVs. Immunoprecipitation-mass spectrometry was utilized to identify proteins interacting with LMP1. The regulatory effects of sEVs on tumor microenvironment were assessed by monitoring CD8<sup>+</sup> T cell proliferation and interferon-γ (IFN-γ) expression via flow cytometry. Furthermore, the expression patterns of LMP1 and downstream regulators in NPC were analyzed using mIF and survival analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>High LMP1 expression in NPC patient specimens and mouse models was associated with restricted infiltration of CD8<sup>+</sup> T cells. Additionally, LMP1 promoted sEV PD-L1 secretion, leading to inhibition of CD8<sup>+</sup> T cell viability and IFN-γ expression in vitro. Mechanistically, LMP1 recruited apoptosis-linked gene 2-interacting protein X (ALIX) through its intracellular domain and bound PD-L1 through its transmembrane domain, thereby facilitating the loading of PD-L1 into ALIX-dependent sEVs. Disruption of ALIX diminished LMP1-induced sEV PD-L1 secretion and enhanced the anti-tumor immunity of CD8<sup>+</sup> T cells both in vitro and in vivo. Moreover, increased expression levels of LMP1 and ALIX were positively correlated with enhanced immunosuppressive features and worse prognostic outcomes in NPC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings uncovered the mechanism by which LMP1 interacts with ALIX and PD-L1 to form a trimolecular complex, facilitating PD-L1 loading int","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1391-1413"},"PeriodicalIF":20.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458711","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":"Exciting progress in targeted therapy innovation for unresectable stage III EGFR-mutated NSCLC: the phase III LAURA study","authors":"Ziyan Tong, Ning Zhu, Hong Shen, Ying Yuan","doi":"10.1002/cac2.12611","DOIUrl":"10.1002/cac2.12611","url":null,"abstract":"<p>Based on the PACIFIC trial (NCT02125461), the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by durvalumab consolidation [<span>1</span>]. However, a subsequent post-hoc analysis revealed no advantage of durvalumab in terms of progression-free survival (PFS) for patients with epidermal growth factor receptor (<i>EGFR</i>) mutations (hazard ratio [HR] = 0.91) [<span>2</span>]. This indicates that “PACIFIC” treatment does not meet the clinical needs of unresectable stage III <i>EGFR</i>-mutated NSCLC patients, who have short PFS and are prone to new metastases.</p><p>The results of the LAURA study (NCT03521154) were recently published in <i>The New England Journal of Medicine</i> [<span>3</span>]. This was a double-blind, randomized, placebo-controlled phase III study that enrolled 216 patients from 145 centers who were diagnosed with unresectable stage III <i>EGFR</i>-mutated NSCLC without disease progression after CRT. They were randomized in a 2:1 ratio to consolidation therapy with osimertinib or placebo until disease progression or death. The primary endpoint was PFS, whereas the secondary endpoints included overall survival (OS), central nervous system PFS, objective response rate (ORR), and safety.</p><p>The LAURA study revealed that osimertinib significantly prolonged the median PFS compared with placebo (39.1 months vs. 5.6 months, HR = 0.16, <i>P</i> < 0.001), with substantial PFS benefits across all subgroups. Moreover, the osimertinib group demonstrated remarkable reductions in new metastases compared to placebo, particularly in the brain (8% vs. 29%) and lung (6% vs. 29%).</p><p>The safety of osimertinib has been closely scrutinized by clinicians and patients. Although there was a higher rate of adverse events (AEs) over grade 3 in the osimertinib group (35% vs. 12%), these events were largely predictable, and there were no new safety concerns. Furthermore, the rate of radiation pneumonitis, which is often the most concerning AE, did not differ significantly between the osimertinib and placebo groups (48% vs. 38%). Overall, the safety was within the expected manageable range.</p><p>For <i>EGFR</i>-mutated NSCLC, previous studies have demonstrated the favorable efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) (Table 1) [<span>4-7</span>]. Osimertinib has been approved as a first-line treatment for stage IV NSCLC and an adjuvant treatment for resectable stage I-III NSCLC. However, for unresectable stage III NSCLC, it remains an unmet clinical need. Recently, an international multicenter real-world study involved 136 patients with unresectable stage III <i>EGFR</i>-mutated NSCLC who received CRT followed by treatment with osimertinib, durvalumab, or observation [<span>8</span>]. Results revealed that osimertinib outperformed durvalumab and observation in real-world median PFS (not reached [NR] vs. 12.7 months vs. 9.7 months), supporting the successful launc","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1381-1384"},"PeriodicalIF":20.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458709","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":"Deciphering protective genomic factors of tumor development in pediatric Down syndrome via deep learning approach to whole genome and RNA sequencing","authors":"Yichuan Liu, Hui-Qi Qu, Xiao Chang, Frank D Mentch, Haijun Qiu, Kenny Nguyen, Kayleigh Ostberg, Tiancheng Wang, Joseph Glessner, Hakon Hakonarson","doi":"10.1002/cac2.12612","DOIUrl":"10.1002/cac2.12612","url":null,"abstract":"<p>Childhood solid tumors represent a significant public health challenge worldwide, with approximately 15,000 new cases annually in the United States and an estimated 300,000 globally. Down syndrome (DS), a genetic disorder characterized by an extra full or partial copy of chromosome 21, results in distinctive developmental and physical features. Notably, individuals with DS exhibit a remarkable resilience against solid tumors compared to the general population, with an overall standardized incidence ratio (SIR) of 0.45, despite their increased susceptibility to hematologic malignancies [<span>1</span>]. This paradoxical observation has spurred extensive research aimed at uncovering the biological underpinnings of this natural resistance to solid cancers. Current theories suggest that the overexpression of specific genes on chromosome 21 may confer protective benefits (e.g. <i>RCAN1</i> contributes to antiangiogenic effects), and alterations in immune system function may enhance apoptosis and DNA repair pathways in individuals with trisomy 21 DS [<span>2</span>]. The well-established epigenetic effects of trisomy 21, which influence the entire genome, are another potential contributor to the reduced risk of solid tumors [<span>3</span>]. Nonetheless, these hypotheses face significant challenges, such as the potential oversimplification of complex genetic interactions and the lack of comprehensive genome-wide analyses. This study seeks to critically evaluate the correlations between genomic variants and cancer clinical phenotypes in patients with DS, and proposes directions for future research into the genetic and molecular mechanisms that confer cancer resistance in DS, potentially transforming our understanding and treatment of pediatric cancers.</p><p>We conducted an innovative unbiased data-driven analysis in 2,452 whole-genome sequencing (WGS) samples with both DS individuals (<i>n</i> = 635) and pediatric oncology cases (<i>n</i> = 280) within the Gabriella Miller Kids First program project (https://kidsfirstdrc.org/) housed at the Children's Hospital of Philadelphia (Supplementary Figure S1). Additionally, 284 RNA sequencing samples from human peripheral blood mononuclear cells (PBMCs), a subset of WGS samples, were also analyzed, offering unprecedented insights into the complex interplay of genetic and immunological factors influencing cancer resistance.</p><p>The importance of each variant was calculated using deep learning algorithms, and their corresponding weights to DS cancer were generated based on linear algebra models as described in the Supplementary Materials and Methods. There were 2,523 unique cancer protective variants identified based on deep learning algorithms combined with linear algebra models in exonic, intronic, non-coding RNA and 5’untranslated region (5’UTR) regions. The prevalence for cancer protective variants in the DS cancer group (89.2%) is significantly higher compared to non-DS cancer individuals (58.1%) (<i>P","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 11","pages":"1374-1378"},"PeriodicalIF":20.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458708","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}