Cancer Communications最新文献

{"title":"Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.","authors":"Yongcan Liu, Shanchun Chen, Xueying Wan, Rui Wang, Haojun Luo, Chao Chang, Peijin Dai, Yubi Gan, Yuetong Guo, Yixuan Hou, Yan Sun, Yong Teng, Xiaojiang Cui, Manran Liu","doi":"10.1002/cac2.12608","DOIUrl":"10.1002/cac2.12608","url":null,"abstract":"<p><strong>Background: </strong>Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.</p><p><strong>Methods: </strong>Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2⁺ MFs) in lung metastasis.</p><p><strong>Results: </strong>We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2⁺ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2⁺ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2⁺ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.</p><p><strong>Conclusions: </strong>Our study reveals crucial roles of TDO2⁺ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1261-1286"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104686","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":"Partial hepatectomy versus interventional treatment in patients with hepatitis B virus-related hepatocellular carcinoma and clinically significant portal hypertension: a randomized comparative clinical trial.","authors":"Yichuan Yuan, Hong Peng, Wei He, Yun Zheng, Jiliang Qiu, Bin Chen, Ruhai Zou, Chenwei Wang, Wan Yee Lau, Binkui Li, Yunfei Yuan","doi":"10.1002/cac2.12614","DOIUrl":"10.1002/cac2.12614","url":null,"abstract":"<p><strong>Background: </strong>The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long-term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre-ablation transarterial chemoembolization (TACE) in patients with HBV-related HCC within the Milan criteria and with clinically significant PHT were compared in this study.</p><p><strong>Methods: </strong>This open-label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)-related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and therapeutic safety.</p><p><strong>Results: </strong>Each of the 2 groups had 80 patients. The 1-, 3- and 5-year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively (P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively (P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P < 0.001). However, the differences were mainly in Clavien-Dindo Grade I complications (P < 0.001), while not significant in Grade II/III/IV/V (All P > 0.05).</p><p><strong>Conclusions: </strong>This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV-related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1337-1349"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342200","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 SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.","authors":"Jialiang Cai, Lina Song, Feng Zhang, Suiyi Wu, Guiqi Zhu, Peiling Zhang, Shiping Chen, Junxian Du, Biao Wang, Yufan Cai, Yi Yang, Jinglei Wan, Jian Zhou, Jia Fan, Zhi Dai","doi":"10.1002/cac2.12607","DOIUrl":"10.1002/cac2.12607","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.</p><p><strong>Methods: </strong>To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids.</p><p><strong>Results: </strong>SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8⁺ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8⁺ T cells and the proportion of interferon-γ⁺CD8⁺ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models.</p><p><strong>Conclusions: </strong>The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1231-1260"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12607","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119068","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":"Altered glycosylation in cancer: molecular functions and therapeutic potential.","authors":"Xuemeng Xu, Qiu Peng, Xianjie Jiang, Shiming Tan, Wenjuan Yang, Yaqian Han, Linda Oyang, Jinguan Lin, Mengzhou Shen, Jiewen Wang, Haofan Li, Longzheng Xia, Mingjing Peng, Nayiyuan Wu, Yanyan Tang, Hui Wang, Qianjin Liao, Yujuan Zhou","doi":"10.1002/cac2.12610","DOIUrl":"10.1002/cac2.12610","url":null,"abstract":"<p><p>Glycosylation, a key mode of protein modification in living organisms, is critical in regulating various biological functions by influencing protein folding, transportation, and localization. Changes in glycosylation patterns are a significant feature of cancer, are associated with a range of pathological activities in cancer-related processes, and serve as critical biomarkers providing new targets for cancer diagnosis and treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) for breast cancer, alpha-fetoprotein (AFP) for liver cancer, carcinoembryonic antigen (CEA) for colon cancer, and prostate-specific antigen (PSA) for prostate cancer are all tumor biomarkers approved for clinical use. Here, we introduce the diversity of glycosylation structures and newly discovered glycosylation substrate-glycosylated RNA (glycoRNA). This article focuses primarily on tumor metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, and cellular senescence to illustrate the role of glycosylation in cancer. Additionally, we summarize the clinical applications of protein glycosylation in cancer diagnostics, treatment, and multidrug resistance. We envision a promising future for the clinical applications of protein glycosylation.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1316-1336"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280530","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":"Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms","authors":"Jiali Yao,&nbsp;Linlin Ji,&nbsp;Guang Wang,&nbsp;Jin Ding","doi":"10.1002/cac2.12613","DOIUrl":"10.1002/cac2.12613","url":null,"abstract":"<p>Neutrophils are key mediators of the immune response and play essential roles in the development of tumors and immune evasion. Emerging studies indicate that neutrophils also play a critical role in the immunotherapy resistance in cancer. In this review, firstly, we summarize the novel classification and phenotypes of neutrophils and describe the regulatory relationships between neutrophils and tumor metabolism, flora microecology, neuroendocrine and tumor therapy from a new perspective. Secondly, we review the mechanisms by which neutrophils affect drug resistance in tumor immunotherapy from the aspects of the immune microenvironment, tumor antigens, and epigenetics. Finally, we propose several promising strategies for overcoming tumor immunotherapy resistance by targeting neutrophils and provide new research ideas in this area.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"15-42"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562643","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":"Tumor derived cell-free nucleic acid upregulates programmed death-ligand 1 expression in neutrophil via intracellular Toll-like receptor signaling","authors":"Suguru Saito,&nbsp;Duo-Yao Cao,&nbsp;Tomohiro Shibata,&nbsp;Yan Liu,&nbsp;Aoi Otagiri-Hoshi,&nbsp;Xiaojiang Cui,&nbsp;Kenneth E. Bernstein","doi":"10.1002/cac2.12615","DOIUrl":"10.1002/cac2.12615","url":null,"abstract":"&lt;p&gt;Neutrophils are innate immune cells that function predominantly against pathogens, while recent studies have revealed additional crucial roles in various diseases, including cancers [&lt;span&gt;1-3&lt;/span&gt;]. For instance, neutrophils expressing the co-inhibitory molecule programmed death-ligand 1 (PD-L1) were identified as novel immunosuppressive myeloid cells that impair cytotoxic T cell (CTL) activity via programmed cell death protein 1 (PD-1)/PD-L1 interaction [&lt;span&gt;4, 5&lt;/span&gt;]. Although some stimuli have been identified, it is still unclear whether the nucleic acid sensing system (NAS) participates in PD-L1 upregulation in neutrophils [&lt;span&gt;6&lt;/span&gt;]. Here, we report that increased cell-free nucleic acid (CFNA) upregulates PD-L1 expression via intracellular Toll-like receptor (TLR) activation in neutrophils following tumor expansion.&lt;/p&gt;&lt;p&gt;Flow cytometry analysis showed that the expression of PD-L1 was gradually increased in peripheral blood (PB) neutrophil after inoculating B16-F10 melanoma cells or EO771 breast cancer cells into wildtype (WT) mice (Figure 1A, protocol is shown in the Supplementary Materials and gating strategy of flow cytometry is shown in Supplementary Figure S1). Notably, the expression of PD-L1 was significantly increased in PB neutrophils of B16-F10-inoculated mice as early as day 3 post-injection compared to those of naïve mice. Although EO771-inoculated mice did not show significantly increased PD-L1 expression in PB neutrophil at days 3 and 7 of post tumor inoculation, there was a significant, pronounced upregulation at day 14 (Figure 1A). Intratumor (IT) neutrophils showed the largest increase of PD-L1 expression compared to neutrophils in PB, spleen and bone marrow (BM) 14 days post inoculation in both types of tumors. The PD-L1 expression level in BM neutrophils was lower than that of PB and spleen neutrophils in B16-F10 inoculated mice. In EO771-inoculated mice, the PD-L1 expression levels in BM and spleen neutrophils were similar, but slightly lower than that in PB (Supplementary Figure S2A and B). Interestingly, similar to the observation in PB, spleen and BM neutrophils also showed significant increases in PD-L1 levels in tumor-bearing mice compared to those of naïve mice, implying that neutrophil PD-L1 upregulation occurs systematically in these murine tumor models (Supplementary Figure S2C and D). Given these data, we decided to investigate circulating factors that may induce changes in PD-L1 levels in neutrophils of tumor-bearing mice, and found that the plasma CFNA levels were significantly increased in the tumor-bearing mice compared to the mice before tumor inoculation (Figure 1B). Linear regression analyses showed strong positive correlations between the plasma CFNA and PB neutrophil-associated PD-L1 expression levels in tumor-bearing mice (Figure 1C). Of note, both the plasma CFNA (Figure 1D) and neutrophil PD-L1 expression levels (Supplementary Figure S3) were positively correlated with the tumor volu","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"4-8"},"PeriodicalIF":20.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543909","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":"Wnt/GSK-3β mediates posttranslational modifications of FLYWCH1 to regulate intestinal epithelial function and tumorigenesis in the colon","authors":"Sheema Almozyan,&nbsp;Roya Babaei-Jadidi,&nbsp;Abrar Aljohani,&nbsp;Sepideh Youssefi,&nbsp;William Dalleywater,&nbsp;Prerna Kadam,&nbsp;Bradley Spencer-Dene,&nbsp;Emad Rakha,&nbsp;Mohammad Ilyas,&nbsp;Abdolrahman Shams Nateri","doi":"10.1002/cac2.12625","DOIUrl":"10.1002/cac2.12625","url":null,"abstract":"&lt;p&gt;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 [&lt;span&gt;1&lt;/span&gt;]. 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 [&lt;span&gt;1&lt;/span&gt;]. FLYWCH-Type Zinc Finger 1 (FLYWCH1), an uncharacterised transcription factor, binds unphosphorylated-β-catenin [&lt;span&gt;2&lt;/span&gt;], is associated with H3K9me3 in (peri)centromeric chromatin [&lt;span&gt;3&lt;/span&gt;], and colocalizes with γ-H2AX foci [&lt;span&gt;4&lt;/span&gt;]. While its deletion is embryonically lethal in mice [&lt;span&gt;5&lt;/span&gt;], the specific role and regulation of FLYWCH1 in tissue homeostasis and tumorigenesis remain unclear.&lt;/p&gt;&lt;p&gt;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).&lt;/p&gt;&lt;p&gt;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 &lt;i&gt;Flywch1&lt;/i&gt;, 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 &lt;i&gt;Flywch1&lt;/i&gt; mRNA on representative brain, liver and intestinal sections from 16-week-old wild-type mice (Supplementary Figure S2A-G). We observed high expression of &lt;i&gt;Flywch1&lt;/i&gt; in cells located alongside the ISC marker Olfactomedin-4 (&lt;i&gt;Olmf4&lt;/i&gt;)-positive cells, while &lt;i&gt;Flywch1&lt;/i&gt; 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 &lt;i&gt;Apc&lt;/i&gt;&lt;sup&gt;Min+/−&lt;/sup&gt; mice, which harbour tumors and adjacent non-tumor regions. &lt;i&gt;Flywch1&lt;/i&gt; 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,&nbsp;Wenjing Ning,&nbsp;Lei Wang,&nbsp;Han Liu,&nbsp;Hongye Zeng,&nbsp;Xiaojing Qin,&nbsp;Yuanzhi Chen,&nbsp;Fentian Chen,&nbsp;Lin Xu,&nbsp;Yang Zhao,&nbsp;Xiaoqing Chen,&nbsp;Jixian Tang,&nbsp;Yunlong Ren,&nbsp;Xiaowen Yan,&nbsp;Wenxin Luo,&nbsp;Ningshao Xia","doi":"10.1002/cac2.12616","DOIUrl":"10.1002/cac2.12616","url":null,"abstract":"&lt;p&gt;The inefficient tumor penetration of conventional antibodies has hampered the effective use of antibody-drug conjugates (ADCs) against solid tumors [&lt;span&gt;1-5&lt;/span&gt;]. 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 [&lt;span&gt;6, 7&lt;/span&gt;]. However, the clinical application of Nb-based ADCs is limited due to the short half-life of the Nbs [&lt;span&gt;8&lt;/span&gt;]. 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) [&lt;span&gt;9&lt;/span&gt;]. 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.&lt;/p&gt;&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;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,&nbsp;Yanfeng Wang,&nbsp;Yanrong Zhu,&nbsp;Tao Wu,&nbsp;Zhenyang Liu,&nbsp;Jin Zhou,&nbsp;Yuan Yuan,&nbsp;Mudan Yang,&nbsp;Bo Liu,&nbsp;Zhenbo Tan,&nbsp;Wu Zhuang,&nbsp;Jiayan Chen,&nbsp;Ning Li,&nbsp;Ying Wang,&nbsp;Xuhui Hu,&nbsp;Lin Wang,&nbsp;Haoyu Yu,&nbsp;Qingyu Wang,&nbsp;Jun Zhu,&nbsp;Jing Huang","doi":"10.1002/cac2.12621","DOIUrl":"10.1002/cac2.12621","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;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.&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;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&lt;sup&gt;2&lt;/sup&gt;, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m&lt;sup&gt;2&lt;/sup&gt;, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and 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;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.&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;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; 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,&nbsp;Sreenidhi Mohanvelu,&nbsp;Dinesh Babu Somasundaram,&nbsp;Sheeja Aravindan,&nbsp;Natarajan Aravindan","doi":"10.1002/cac2.12620","DOIUrl":"10.1002/cac2.12620","url":null,"abstract":"&lt;p&gt;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) [&lt;span&gt;1&lt;/span&gt;], 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 (&lt; 10% long term overall survival [OS]) in high-risk NB that contributes to about 10% of all childhood cancer deaths [&lt;span&gt;2&lt;/span&gt;]. 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 [&lt;span&gt;2, 3&lt;/span&gt;]. However, these protective responses can take an impromptu turn in favor of tumor progression in immune-compromised individuals, and those tumors with lower immunogenicity [&lt;span&gt;4&lt;/span&gt;]. This establishes cancer immune editing within the TME leading to acquired tumor immune evasion (TIME) that substantially contributes to cancer evolution and poor outcomes [&lt;span&gt;2, 4, 5&lt;/span&gt;]. 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 [&lt;span&gt;6, 7&lt;/span&gt;]; 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 [&lt;span&gt;8, 9&lt;/span&gt;]. Assessing the function of RD3 in NB TIME (Figure 1), here we recognized the unique requirement for RD3 to maintain NB immune surveillance.&lt;/p&gt;&lt;p&gt;The immune microenvironment enclosed within the TME plays a discrete role in tumor immune surveillance. CIBERSORTx analysis (&lt;i&gt;P&lt;/i&gt; &lt; 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 [&lt;span&gt;10&lt;/span&gt;] in RD3 reverse engineered (RD3-knockout) three unique models inflicted a “model-dependent” loss (vs. RD3&lt;sup&gt;+&lt;/sup&gt;) 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&lt;sub&gt;0&lt;/sub&gt;, M&lt;sub&gt;1&lt;/sub&gt;, and M&lt;sub&gt;2&lt;/sub&gt; macrophages, resting and activated mast cells, eosinophils and, a “model-independent” loss (vs. RD3&lt;sup&gt;+&lt;/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}