Cancer research communications最新文献

{"title":"A Cost-Effective Two-Step Approach for Multi-Cancer Early Detection in High-Risk Populations.","authors":"Shuaipeng Geng, Shiyong Li, Wei Wu, Yinyin Chang, Mao Mao","doi":"10.1158/2767-9764.CRC-24-0508","DOIUrl":"10.1158/2767-9764.CRC-24-0508","url":null,"abstract":"<p><strong>Abstract: </strong>In population-wide cancer screening, three key issues need to be focused on: the number of cancer cases identified, the number of false positives, and the cost. OncoSeek is a multi-cancer early detection (MCED) test using seven protein tumor markers and artificial intelligence. SeekInCare is an MCED test that integrates the seven protein tumor markers and four cancer genomic features from cell-free DNA by shallow whole-genome sequencing. In a two-step approach, the initial screening is conducted using OncoSeek, and SeekInCare is then used as the secondary test for individuals who tested positive by OncoSeek. We simulated a screening in five million adults ages ≥50 years with a cancer incidence rate of 1.9%. Whereas at 91.0% specificity OncoSeek had 441,450 false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although SeekInCare and Galleri identified more cancer cases (32,015 and 27,455, respectively) than the two-step MCED (21,280), their total costs reached $3,750 million and $4,745 million, respectively. As the positive predictive value of two-step MCED (38.3%) was comparable with SeekInCare (27.7%) and Galleri (38.3%), it reduced the cost by 5.3-fold and 6.6-fold, respectively, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected was $117,133 for SeekInCare and $172,828 for Galleri, which were 3.5-fold and 5.2-fold higher, respectively, than the two-step MCED ($33,534). The two-step approach not only significantly reduces false positives but also cuts down the screening cost substantially, making it a cost-effective strategy for population-wide cancer screening.</p><p><strong>Significance: </strong>Large-scale screening inevitably leads to significant financial burdens on the healthcare system, which is a key factor constraining nationwide screenings. The two-step MCED approach not only maintains comparable performance but also substantially alleviates financial strains compared with the direct use of next-generation sequencing-based MCED tests for massive screenings.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"150-156"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Study of 23ME-00610, an Antagonistic Antibody for Genetically Validated CD200R1 Immune Checkpoint, in Participants with Advanced Solid Malignancies.","authors":"Shivaani Kummar, Albiruni Abdul Razak, Scott Laurie, Dylan M Glatt, Sariah Kell, Anh N Diep, Maike Schmidt, Clifford Hom, Chris German, Suyash S Shringarpure, Sophia R Majeed, Drew Rasco","doi":"10.1158/2767-9764.CRC-24-0568","DOIUrl":"10.1158/2767-9764.CRC-24-0568","url":null,"abstract":"<p><strong>Purpose: </strong>In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety.</p><p><strong>Patients and methods: </strong>Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg.</p><p><strong>Results: </strong>Twenty-eight participants were enrolled across seven cohorts and received a median of four cycles of 23ME-00610. No treatment-related serious adverse events (AE) were observed, and the maximum tolerated dose was not reached. Overall, the PK of 23ME-00610 was linear and dose proportional for doses ≥60 mg, with a median terminal half-life of 13 days at 1,400 mg. Peripheral saturation of CD200R1 was observed for doses ≥60 mg. Immune-related AEs, including rash, pruritus, and hypothyroidism, were predicted by phenome-wide association studies and observed for doses ≥60 mg. A confirmed partial response was observed in a participant with well-differentiated pancreatic neuroendocrine cancer whose tumor was among those with the highest tumor CD200 expression.</p><p><strong>Conclusions: </strong>23ME-00610 has mild-to-moderate on-target AEs and PK/PD consistent with tumor target saturation and dosing every 3 weeks. The trend for clinical benefit in participants with tumor CD200 expression suggests that 23ME-00610 inhibits CD200R1 signaling and may reverse CD200-mediated immune evasion. Based on PK/PD, safety, and preliminary antitumor activity, 1,400 mg Q3W was selected as the dose for further study.</p><p><strong>Significance: </strong>Genome-wide association studies (GWAS) of the 23andMe genetic database identified CD200R1 as a promising therapeutic target for cancer. This phase 1 study of 23ME-00610, a CD200R1 antagonist IgG1, showed acceptable safety and tolerability, PK supporting Q3W dosing, and PD and preliminary clinical activity supporting an initial recommended phase 2 dose of 1,400 mg.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"94-105"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PRMT1 Reduces Cancer Persistence and Tumor Relapse in EGFR- and KRAS-Mutant Lung Cancer.","authors":"Xiaoxiao Sun, Karl Kumbier, Savitha Gayathri, Veronica Steri, Lani F Wu, Steven J Altschuler","doi":"10.1158/2767-9764.CRC-24-0389","DOIUrl":"10.1158/2767-9764.CRC-24-0389","url":null,"abstract":"<p><strong>Abstract: </strong>Incomplete killing of cancer cells undermines oncogene-targeting therapies and drives disease relapse. Eliminating cancer cells that persist during treatment is crucial for improving treatment outcomes. Here, we discovered that a specific isoform of type I protein arginine methyltransferases (PRMT), namely, PRMT1, enables lung cancer cells with EGFR or KRASG12C driver mutations and high STAT1 activity to persist through targeted drug treatments. PRMT1 knockdown, combined with EGFR or KRASG12C inhibitors, decreased persistence and delayed cancer cell regrowth across cell line models and significantly prolonged tumor regression in xenograft models. In contrast, we found that knockdown of two other type I PRMT isoforms, PRMT4 and PRMT6, increased persistence. Finally, we found that targeting PRMT1 to reduce persistence is more effective in lung cancer models with intact versus deleted chromosome 5q31.1, a region enriched with JAK-STAT pathway genes, suggesting a potential stratification criterion. Together, our study pinpoints the PRMT1 isoform as a critical vulnerability of cancer persistence in EGFR- or KRASG12C-targeted therapies.</p><p><strong>Significance: </strong>Eliminating \"persisters\" before relapse is crucial for achieving durable treatment efficacy. This study provides a rationale for developing PRMT1-selective inhibitors to target cancer persisters and achieve more durable outcomes in oncogene-targeting therapies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"119-127"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Tumor Immune Microenvironment and Therapeutic Efficacy of Trastuzumab Deruxtecan in Gastric Cancer.","authors":"Shigehiro Koganemaru, Shohei Koyama, Fumitaka Suto, Makito Koga, Koichiro Inaki, Yusuke Kuwahara, Takeo Arita, Tsuyoshi Hirata, Hiroki Goto, Naoya Wada, Maki Kobayashi, Tomoko Shibutani, Tatsuya Okabayashi, Kenji Nakamaru, Akihito Kawazoe, Yousuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara","doi":"10.1158/2767-9764.CRC-24-0302","DOIUrl":"10.1158/2767-9764.CRC-24-0302","url":null,"abstract":"<p><strong>Abstract: </strong>Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody–drug conjugate with a topoisomerase I inhibitor connected by a cleavable linker, has been approved for patients with HER2-positive gastric or gastroesophageal junction tumors. This biomarker study assessed HER2 expression and immune cell infiltration in relation to the therapeutic response to T-DXd. This retrospective analysis included samples from patients treated with T-DXd in three clinical trials. We performed RNA sequencing and multiplex IHC on archival tumor samples obtained at baseline, during treatment, and after treatment. Flow cytometry was performed on tumor-infiltrating immune cells freshly isolated from tumor tissues. Samples from 28 patients were included in this study. ERBB2 mRNA levels and CD20+ cell infiltration in tumors were significantly higher at baseline in responders than in nonresponders. Patients were classified into three biological groups based on their baseline tumor/stroma-infiltrating immune cell densities. Two groups reported similar response rates, but a trend was observed toward a shorter progression-free survival in the group with more immunosuppressive regulatory T cells and PD-L1 expression at baseline. T-DXd treatment tended to increase the levels of tumor-infiltrating CD8+ T cells and PD1+CD8+ T cells, particularly in responders. Gene expression signatures of CTL and Th cells increased during treatment, whereas signatures related to hypoxia, MYC targets, collagen formation, and IL-10 were downregulated. Our data suggest that HER2 expression levels and baseline tumor microenvironment characteristics correlate with T-DXd efficacy. Furthermore, this treatment may modulate tumor microenvironment immune profiles. Further validation using a larger sample size is warranted.</p><p><strong>Significance: </strong>This biomarker study explored HER2 expression levels and immune cell characteristics that may affect response to T-DXd using tumor tissue samples collected from clinical trial participants. The results suggest that HER2 expression levels and tumor characteristics before the initiation of T-DXd may correlate with the efficacy of the drug.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"84-93"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating Ovarian Cancer Risk-Reducing Salpingectomy Acceptance: A Survey.","authors":"Alexandra Lukey, Ramlogan Sowamber, David Huntsman, Celeste Leigh Pearce, A Fuchsia Howard, Rafael Meza, Michael R Law, Minh Tung Phung, Gillian E Hanley","doi":"10.1158/2767-9764.CRC-24-0566","DOIUrl":"10.1158/2767-9764.CRC-24-0566","url":null,"abstract":"<p><strong>Abstract: </strong>With evidence that salpingectomy is effective in preventing high-grade serous carcinoma, it is time to consider offering this procedure to people at higher-than-average lifetime risk for ovarian cancer, despite not having a pathogenic genetic variant that increases the risk for ovarian cancer. This targeted approach has potential to be effective at reducing ovarian cancer incidence, and unlike opportunistic salpingectomy, it is focused on people with an increased lifetime risk of ovarian cancer. However, the acceptability of this approach within the population of potential patients remains unknown. We conducted an online survey of adults in British Columbia, Canada, who were defined as “at risk” for ovarian cancer (i.e., people born with ovaries). Participants completed a questionnaire on demographics, ovarian cancer risk and protective factors, concerns about risk-reducing salpingectomy (RSS), and the risk they considered high enough to warrant RRS. We included 211 participants. Among these participants, 42% (n = 88) indicated that they would consider RRS at any lifetime risk or any risk above the population average. Another 20 participants chose risks between 1.5% and 4% for a cumulative 51% of the sample choosing risks below thresholds for oophorectomy. In contrast, 6% (n = 12) indicated that they would not consider the procedure at any risk level. None of the factors collected were associated with the likelihood that a person would find RRS acceptable. Overall, our participants showed broad interest in RRS as an ovarian cancer prevention strategy. These results suggest that there would likely be uptake if RRS was offered.</p><p><strong>Significance: </strong>This study found that many participants were willing to consider RRS to prevent ovarian cancer. Further research on RRS should be undertaken to understand how this can be best used for ovarian cancer prevention.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"187-194"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Synergistic Effect between Niraparib and Statins in Ovarian Cancer Clinical Trials.","authors":"Hailei Zhang, Anna Rutkowska, Antonio González-Martín, Mansoor R Mirza, Bradley J Monk, Ignace Vergote, Bhavana Pothuri, Whitney A Spannuth Graybill, Carsten Goessel, Olena Barbash, Giovanna Bergamini, Bin Feng","doi":"10.1158/2767-9764.CRC-24-0191","DOIUrl":"10.1158/2767-9764.CRC-24-0191","url":null,"abstract":"<p><strong>Abstract: </strong>This study investigates the potential clinical synergy between the PARP inhibitor niraparib (Zejula) and concomitant statins, exploring their combined effects on progression-free survival (PFS) in patients with ovarian cancer. We retrospectively analyzed niraparib registrational clinical trials in ovarian cancer to investigate potential interactions between niraparib and statins. In the PRIMA trial, patients receiving niraparib demonstrated improved PFS compared with those on placebo (HR = 0.62; P < 0.001; median PFS 13.8 vs. 8.2 months). The post hoc analysis revealed that patients receiving maintenance niraparib who reported concomitant use of statins exhibited significantly improved PFS compared with those on placebo with concomitant statins (HR = 0.34; P < 0.001; median PFS 18.2 vs. 6.0 months). Notably, the improved efficacy in the two-arm comparison of concomitant statin patients was much better than that in the two-arm comparison of those patients without statin, as reflected in the niraparib–statin interaction (P = 0.005). These findings suggest novel opportunities in oncology for the use of statins in combination therapies with PARP inhibitors and emphasize the need for further investigation.</p><p><strong>Significance: </strong>The presented retrospective analysis suggests, to the best of our knowledge for the first time, a potential significant interaction between statins and niraparib in clinical settings. Nevertheless, further investigations are required to gain a better understanding of the potential clinical benefit.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"178-186"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Proteomics Reveals Vulnerabilities in Noninvasive Breast Ductal Carcinoma and Drives Personalized Treatment Strategies.","authors":"Georgia Mitsa, Livia Florianova, Josiane Lafleur, Adriana Aguilar-Mahecha, Rene P Zahedi, Sonia V Del Rincon, Mark Basik, Christoph H Borchers, Gerald Batist","doi":"10.1158/2767-9764.CRC-24-0287","DOIUrl":"10.1158/2767-9764.CRC-24-0287","url":null,"abstract":"<p><strong>Abstract: </strong>Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions in women. The lack of validated prognostic markers, limited patient numbers, and variable tissue quality have a significant impact on the diagnosis, risk stratification, patient enrollment, and results of clinical studies. In this study, we performed label-free quantitative proteomics on 50 clinical formalin-fixed, paraffin-embedded biopsies, validating 22 putative biomarkers from independent genetic studies. Our comprehensive proteomic phenotyping reveals more than 380 differentially expressed proteins and metabolic vulnerabilities, which can inform new therapeutic strategies for DCIS and invasive ductal carcinoma. Due to the readily druggable nature of proteins and metabolic enzymes or metabolism inhibitors, this study is of high interest for clinical research and the pharmaceutical industry. To further evaluate our findings, and to promote the clinical translation of our study, we developed a highly multiplexed targeted proteomics assay for 90 proteins associated with cancer metabolism, RNA regulation, and signature cancer pathways, such as PI3K/AKT/mTOR and EGFR/RAS/RAF.</p><p><strong>Significance: </strong>This study provides real-world evidence for DCIS, a disease for which currently no molecular tools or biomarkers exist, and gives an unbiased, comprehensive, and deep proteomic profile, identifying >380 actionable targets.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"138-149"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense Mutant p53 Transactivates Wnt/β-Catenin Signaling in Neighboring p53-Destabilized Cells through the COX-2/PGE2 Pathway.","authors":"Mizuho Nakayama, Hiroshi Saito, Kazuhiro Murakami, Hiroko Oshima, Masanobu Oshima","doi":"10.1158/2767-9764.CRC-24-0471","DOIUrl":"10.1158/2767-9764.CRC-24-0471","url":null,"abstract":"<p><strong>Abstract: </strong>Missense-type p53 mutations have shown to acquire novel oncogenic roles through a gain-of-function mechanism. However, there is intratumor heterogeneity in stabilization of mutant p53 protein, and it has not been well understood about the interaction between p53-stabilized and -destabilized cells in the same tumors. We established mouse intestinal tumor–derived organoids carrying ApcΔ716, KrasG12D, and Tgfbr2−/− mutations with Trp53R270H or Trp53Null mutation (AKTPR270H and AKTPNull, respectively). Using these organoids, we found that the activation level of Wnt/β-catenin signaling is significantly higher in AKTPR270H cells compared with AKTPNull cells. Notably, Wnt activation in the AKTPNull cells was significantly increased when co-cultured with AKTPR270H cells. Expression analysis revealed that COX-2 is significantly upregulated in AKTPR270H but not in AKTPNull cells, suggesting that mutant p53 induces the COX-2/prostaglandin E2 (PGE2) pathway. Importantly, Wnt activation in co-cultured AKTPNull cells with AKTPR270H was significantly suppressed when treated with the inhibitor of COX-2 or PGE2 receptors EP2/EP4. Furthermore, stimulation with PGE2 increased Wnt signaling activity in AKTPNull cells. These results indicate that the COX-2/PGE2 pathway is activated in the p53-stabilized cells in the missense-type p53-mutant cancer, and secreted PGE2 may transactivate Wnt/β-catenin signaling in neighboring p53-destabilized tumor cells in the intratumor microenvironment. Therefore, targeting stabilized mutant p53 or the COX-2/PGE2 pathway may suppress Wnt/β-catenin signaling of both mutant p53–stabilized and –destabilized cells; thus, this can be a possible preventive or therapeutic strategy.</p><p><strong>Significance: </strong>There is intratumor heterogeneity in the stabilization of missense mutant p53, and it has been thought that only cells with nuclear accumulation of mutant p53 have oncogenic function. However, using mouse intestinal tumor-derived organoids, we show that mutant p53-stabilized cells transactivate Wnt/β-catenin signaling in neighboring p53-destabilized cells through activating the COX-2/PGE2 pathway. These results suggest that both p53-stabilized cells and p53-destabilized cells contribute to malignant progression through interaction within the intratumor microenvironment.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"13-23"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depletion of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy.","authors":"Joseph Rupert, Alexes Daquinag, Yongmei Yu, Yulin Dai, Zhongming Zhao, Mikhail G Kolonin","doi":"10.1158/2767-9764.CRC-24-0298","DOIUrl":"10.1158/2767-9764.CRC-24-0298","url":null,"abstract":"<p><strong>Abstract: </strong>Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of subpopulations of cancer-associated fibroblasts (CAF) on cancer progression and therapy resistance are incompletely understood. In this study, the roles of CAFs expressing platelet-derived growth factor receptor β (Pdgfrb) and of CAFs expressing markers of adipose stromal cells (ASC) were analyzed in mice with pancreatic ductal adenocarcinoma. Ablation of Pdgfrb+ cells resulted in suppression of primary pancreatic tumor growth, reduction of extracellular matrix deposition, and increased cancer cell metastasis to the liver. A peptide D-CAN, which induces apoptosis in ASC-like CAFs, also reduced pancreatic tumor growth and extracellular matrix deposition while promoting metastases. Single-cell RNA sequencing demonstrated that depletion of either Pdgfrb+ or ASC-like CAFs decreased frequencies of tumor endothelial cells and viable cancer cells. However, whereas depletion of Pdgfrb+ CAFs led to stronger induction of cancer cell aggressiveness markers, depletion of ASC-like CAFs had an opposite effect on remaining CAFs. Depletion of ASC-like CAFs using D-CAN also led to higher infiltration of cytotoxic T-lymphocytes and B-lymphocytes. Administration of anti-PDL1 antibody (aPDL1), which inhibits the immune checkpoint, had a stronger suppressive effect on tumor growth when combined with D-CAN in both female and male mice. Liver metastases were also reduced by the D-CAN/aPDL1 combination more effectively than by aPDL1 alone in female mice. We conclude that improved approaches to target ASC-like CAFs may be effective in combination with immunotherapy.</p><p><strong>Significance: </strong>This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"5-12"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autofluorescence Virtual Staining System for H&E Histology and Multiplex Immunofluorescence Applied to Immuno-Oncology Biomarkers in Lung Cancer.","authors":"Jessica Loo, Marc Robbins, Carson McNeil, Tadayuki Yoshitake, Charles Santori, Chuanhe Jay Shan, Saurabh Vyawahare, Hardik Patel, Tzu Chien Wang, Robert Findlater, David F Steiner, Sudha Rao, Michael Gutierrez, Yang Wang, Adrian C Sanchez, Raymund Yin, Vanessa Velez, Julia S Sigman, Patricia Coutinho de Souza, Hareesh Chandrupatla, Liam Scott, Shamira S Weaver, Chung-Wein Lee, Ehud Rivlin, Roman Goldenberg, Suzana S Couto, Peter Cimermancic, Pok Fai Wong","doi":"10.1158/2767-9764.CRC-24-0327","DOIUrl":"10.1158/2767-9764.CRC-24-0327","url":null,"abstract":"<p><strong>Abstract: </strong>Virtual staining for digital pathology has great potential to enable spatial biology research, improve efficiency and reliability in the clinical workflow, as well as conserve tissue samples in a nondestructive manner. In this study, we demonstrate the feasibility of generating virtual stains for hematoxylin and eosin (H&E) and a multiplex immunofluorescence (mIF) immuno-oncology panel (DAPI, PanCK, PD-L1, CD3, and CD8) from autofluorescence (AF) images of unstained non–small cell lung cancer tissue by combining high-throughput hyperspectral fluorescence microscopy and machine learning. Using domain-specific computational methods, we evaluated the accuracy of virtual H&E staining for histologic subtyping and virtual mIF for cell segmentation–based measurements, including clinically relevant measurements such as tumor area, T-cell density, and PD-L1 expression (tumor proportion score and combined positive score). The virtual stains reproduce key morphologic features and protein biomarker expressions at both tissue and cell levels compared with real stains, enable the identification of key immune phenotypes important for immuno-oncology, and show moderate to good performance across various evaluation metrics. This study extends our previous work on virtual staining from AF in liver disease and prostate cancer, further demonstrating the generalizability of this deep learning technique to a different disease (lung cancer) and stain modality (mIF).</p><p><strong>Significance: </strong>We extend the capabilities of virtual staining from AF to a different disease and stain modality. Our work includes newly developed virtual stains for H&E and a multiplex immunofluorescence panel (DAPI, PanCK, PD-L1, CD3, and CD8) for non-small cell lung cancer, which reproduce the key features of real stains.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"54-65"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}