NPJ Precision Oncology最新文献

{"title":"Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants","authors":"Richard Gallon, Carlijn Brekelmans, Marie Martin, Vincent Bours, Esther Schamschula, Albert Amberger, Martine Muleris, Chrystelle Colas, Jeroen Dekervel, Gert De Hertogh, Jérôme Coupier, Orphal Colleye, Edith Sepulchre, John Burn, Hilde Brems, Eric Legius, Katharina Wimmer","doi":"10.1038/s41698-024-00603-z","DOIUrl":"10.1038/s41698-024-00603-z","url":null,"abstract":"Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00603-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094068","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":"Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis","authors":"Behnam Ebrahimi, Suryavathi Viswanadhapalli, Uday P. Pratap, Gopalam Rahul, Xue Yang, Prabhakar Pitta Venkata, Viktor Drel, Bindu Santhamma, Swapna Konda, Xiaonan Li, Alondra Lee Rodriguez Sanchez, Hui Yan, Gangadhara R. Sareddy, Zhenming Xu, Brij B. Singh, Philip T. Valente, Yidong Chen, Zhao Lai, Manjeet Rao, Edward R. Kost, Tyler Curiel, Rajeshwar R. Tekmal, Hareesh B. Nair, Ratna K. Vadlamudi","doi":"10.1038/s41698-024-00612-y","DOIUrl":"10.1038/s41698-024-00612-y","url":null,"abstract":"Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00612-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094069","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 resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer","authors":"Thomas F. Cyberski, Alka Singh, Michael Korzinkin, Vasudha Mishra, Frank Pun, Le Shen, Claudia Wing, Xiangying Cheng, Brandon Baird, Yuxuan Miao, Moshe Elkabets, Sara Kochanny, Wenji Guo, Emma Dyer, Alexander T. Pearson, Aditya Juloori, Mark Lingen, Grayson Cole, Alex Zhavoronkov, Nishant Agrawal, Evgeny Izumchenko, Ari J. Rosenberg","doi":"10.1038/s41698-024-00606-w","DOIUrl":"10.1038/s41698-024-00606-w","url":null,"abstract":"The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00606-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088274","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":"Deep learning for dual detection of microsatellite instability and POLE mutations in colorectal cancer histopathology","authors":"Marco Gustav, Nic Gabriel Reitsam, Zunamys I. Carrero, Chiara M. L. Loeffler, Marko van Treeck, Tanwei Yuan, Nicholas P. West, Philip Quirke, Titus J. Brinker, Hermann Brenner, Loëtitia Favre, Bruno Märkl, Albrecht Stenzinger, Alexander Brobeil, Michael Hoffmeister, Julien Calderaro, Anaïs Pujals, Jakob Nikolas Kather","doi":"10.1038/s41698-024-00592-z","DOIUrl":"10.1038/s41698-024-00592-z","url":null,"abstract":"In the spectrum of colorectal tumors, microsatellite-stable (MSS) tumors with DNA polymerase ε (POLE) mutations exhibit a hypermutated profile, holding the potential to respond to immunotherapy similarly to their microsatellite-instable (MSI) counterparts. Yet, due to their rarity and the associated testing costs, systematic screening for these mutations is not commonly pursued. Notably, the histopathological phenotype resulting from POLE mutations is theorized to resemble that of MSI. This resemblance not only could facilitate their detection by a transformer-based Deep Learning (DL) system trained on MSI pathology slides, but also indicates the possibility for MSS patients with POLE mutations to access enhanced treatment options, which might otherwise be overlooked. To harness this potential, we trained a Deep Learning classifier on a large dataset with the ground truth for microsatellite status and subsequently validated its capabilities for MSI and POLE detection across three external cohorts. Our model accurately identified MSI status in both the internal and external resection cohorts using pathology images alone. Notably, with a classification threshold of 0.5, over 75% of POLE driver mutant patients in the external resection cohorts were flagged as “positive” by a DL system trained on MSI status. In a clinical setting, deploying this DL model as a preliminary screening tool could facilitate the efficient identification of clinically relevant MSI and POLE mutations in colorectal tumors, in one go.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00592-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088277","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":"Metabolic pathway-based subtypes associate glycan biosynthesis and treatment response in head and neck cancer","authors":"Benedek Dankó, Julia Hess, Kristian Unger, Daniel Samaga, Christoph Walz, Axel Walch, Na Sun, Philipp Baumeister, Peter Y. F. Zeng, Franziska Walter, Sebastian Marschner, Richard Späth, Olivier Gires, Timm Herkommer, Ramin Dazeh, Thaina Matos, Lisa Kreutzer, Johann Matschke, Katharina Eul, Frederick Klauschen, Ulrike Pflugradt, Martin Canis, Ute Ganswindt, Joe S. Mymryk, Barbara Wollenberg, Anthony C. Nichols, Claus Belka, Horst Zitzelsberger, Kirsten Lauber, Martin Selmansberger","doi":"10.1038/s41698-024-00602-0","DOIUrl":"10.1038/s41698-024-00602-0","url":null,"abstract":"Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous malignancy that remains a significant challenge in clinical management due to frequent treatment failures and pronounced therapy resistance. While metabolic dysregulation appears to be a critical factor in this scenario, comprehensive analyses of the metabolic HNSCC landscape and its impact on clinical outcomes are lacking. This study utilized transcriptomic data from four independent clinical cohorts to investigate metabolic heterogeneity in HNSCC and define metabolic pathway-based subtypes (MPS). In HPV-negative HNSCCs, MPS1 and MPS2 were identified, while MPS3 was enriched in HPV-positive cases. MPS classification was associated with clinical outcome post adjuvant radio(chemo)therapy, with MPS1 consistently exhibiting the highest risk of therapeutic failure. MPS1 was uniquely characterized by upregulation of glycan (particularly chondroitin/dermatan sulfate) metabolism genes. Immunohistochemistry and pilot mass spectrometry imaging analyses confirmed this at metabolite level. The histological context and single-cell RNA sequencing data identified the malignant cells as key contributors. Globally, MPS1 was distinguished by a unique transcriptomic landscape associated with increased disease aggressiveness, featuring motifs related to epithelial-mesenchymal transition, immune signaling, cancer stemness, tumor microenvironment assembly, and oncogenic signaling. This translated into a distinct histological appearance marked by extensive extracellular matrix remodeling, abundant spindle-shaped cancer-associated fibroblasts, and intimately intertwined populations of malignant and stromal cells. Proof-of-concept data from orthotopic xenotransplants replicated the MPS phenotypes on the histological and transcriptome levels. In summary, this study introduces a metabolic pathway-based classification of HNSCC, pinpointing glycan metabolism-enriched MPS1 as the most challenging subgroup that necessitates alternative therapeutic strategies.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00602-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088280","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":"Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib","authors":"Vincent D. de Jager, Jos A. Stigt, Maarten Niemantsverdriet, Arja ter Elst, Anthonie J. van der Wekken","doi":"10.1038/s41698-024-00607-9","DOIUrl":"10.1038/s41698-024-00607-9","url":null,"abstract":"Precision cancer medicine has changed the treatment paradigm of patients with non-small cell lung cancer (NSCLC) with specific molecular aberrations. A major challenge is management of the resistance that tumor cells eventually develop against targeted therapies, either through primary or acquired resistance mechanisms. We report a 61 year-old male patient with metastatic NSCLC harboring an EGFR exon 19 deletion, a PIK3CA mutation, and CDK4 amplification. After an initial partial response to osimertinib as mono-therapy (third-generation EGFR tyrosine kinase inhibitor), the patient had progression of disease after 4 months of treatment and was referred for combined osimertinib and palbociclib (CDK4/6 inhibitor) treatment. Though complicated by transient pneumonitis, the patient has an ongoing partial response for > 10 months and has experienced clinical improvement on this treatment regimen. As amplification of CDK4 occurs in ~ 10% of treatment-naïve patients with EGFR-mutated NSCLC, the successful treatment of our patient with osimertinib and palbociclib may be highly relevant for future patients with NSCLC.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082142","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":"Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog and NIPAL1","authors":"Heidi G. Parker, Alexander C. Harris, Jocelyn Plassais, Deepika Dhawan, Erika M. Kim, Deborah W. Knapp, Elaine A. Ostrander","doi":"10.1038/s41698-024-00591-0","DOIUrl":"10.1038/s41698-024-00591-0","url":null,"abstract":"Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12–22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141082141","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":"Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion","authors":"Sang-Hyun Lee, Kyuhwan Kim, Eunyoung Lee, Kyungmin Lee, Kyeong Hwan Ahn, Hansom Park, Yelim Kim, Soeun Shin, Sang Youl Jeon, Yongki Hwang, Dong Hyuck Ahn, Yong-Jun Kwon, Seok Whan Moon, Mi Hyoung Moon, Kyung Soo Kim, Kwanyong Hyun, Tae-Jung Kim, Yeoun Eun Sung, Joon Young Choi, Chan Kwon Park, Sung Won Kim, Chang Dong Yeo, Hyun-Jung Sohn, You-Seok Hyun, Tai-Gyu Kim, Bosung Ku, Jeong Uk Lim, Seung Joon Kim","doi":"10.1038/s41698-024-00609-7","DOIUrl":"10.1038/s41698-024-00609-7","url":null,"abstract":"Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11109121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076333","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":"Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome","authors":"Hana Palova, Anirban Das, Petra Pokorna, Viera Bajciova, Zdenek Pavelka, Marta Jezova, Karol Pal, Jose R. Dimayacyac, Logine Negm, Lucie Stengs, Vanessa Bianchi, Klara Vejmelkova, Kristyna Noskova, Marie Jarosova, Sona Mejstrikova, Peter Mudry, Michal Kyr, Tomas Merta, Pavel Tinka, Klara Drabova, Stefania Aulicka, Robin Jugas, Uri Tabori, Ondrej Slaby, Jaroslav Sterba","doi":"10.1038/s41698-024-00597-8","DOIUrl":"10.1038/s41698-024-00597-8","url":null,"abstract":"Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11109258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076396","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":"Redirecting NK cells to the lymph nodes to augment their lymphoma-targeting capacity","authors":"Laura Sanz-Ortega, Caroline Leijonhufvud, Lisanne Schoutens, Mélanie Lambert, Emily Levy, Agneta Andersson, Björn E. Wahlin, Mattias Carlsten","doi":"10.1038/s41698-024-00595-w","DOIUrl":"10.1038/s41698-024-00595-w","url":null,"abstract":"CAR-NK cells can induce remission in lymphoma patients. We speculate that the full potential of adoptive NK cell immunotherapy against lymphoma is restricted by their poor lymph node (LN) homing capacity. Here, we have utilized a clinically approved transfection method with the aim of redirecting NK cells to LNs. Electroporation of ex vivo expanded NK cells with mRNAs coding for CCR7, CXCR5, and CD62L resulted in increased in vitro migration towards chemokines and mouse LN-derived supernatant. Following infusion into SCID/Beige mice, modified NK cells showed enhanced LN homing. Importantly, lymphoma patient-derived NK cells were equally well expanded and engineered as healthy donor NK cells, highlighting their translational potential. Additionally, the introduction of high-affinity CD16, together with the homing molecules, also augmented their ADCC capacity against autologous lymphoma cells. Hence, genetic engineering can be utilized to enhance NK cell LN homing. The homing concept may synergize with CAR- or monoclonal/bi-/tri-specific antibody-based approaches.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071552","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}