Cancer immunology research最新文献

{"title":"Artificial Intelligence Can Predict Personalized Immunotherapy Outcomes in Cancer.","authors":"Ling Huang, Xuewei Wu, Jingjing You, Zhe Jin, Wenle He, Jie Sun, Hui Shen, Xin Liu, Xin Yue, Wenli Cai, Shuixing Zhang, Bin Zhang","doi":"10.1158/2326-6066.CIR-24-1270","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1270","url":null,"abstract":"<p><p>The rapid advancement of artificial intelligence (AI) technologies has opened new avenues for advancing personalized immunotherapy in cancer treatment. This review highlights current research progress in applying AI to optimize the use of immunotherapy for patients with cancer. Recent studies demonstrate that AI models can accurately diagnose cancers and discover biomarkers by integrating multi-omics and imaging data, establish predictive models to estimate treatment responses and adverse reactions, formulate personalized treatment plans integrating multiple modalities by considering various factors, and achieve precise patient stratification and clinical trial matching, thereby addressing specific obstacles throughout processes from diagnosis to treatment in personalized immunotherapy. Furthermore, this review also discusses the challenges and limitations faced by AI in clinical applications, such as difficulties in data acquisition, low quality of data, poor interpretability of models, and insufficient generalization ability. Finally, we outline future research directions, including optimizing data management, developing explainable AI, and improving the generalization ability of models. These efforts aim to optimize the role of AI in personalized immunotherapy and promote the development of precision medicine. To ensure the clinical applicability of these AI models, large-scale studies, multi-omics integration, and prospective clinical trials are necessary.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":8.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained macrophage reprogramming is required for CD8+ T cell-dependent long-term tumor eradication.","authors":"Carolina Jardim, Marta Bica, Mariana Reis-Sobreiro, Afonso Teixeira da Mota, Raquel Lopes, Miguel Ferreira Pinto, Neuza Sousa, Sofia Mensurado, Henning Boekhoff, Tommaso Scolaro, Maud Reugebrink, Natacha Goncalves-Sousa, Hiroshi Kubo, Catarina Monteiro Gomes, Catarina Brito, Rafael Argüello, Elvira P Leites, Vanessa A Morais, Bruno Silva-Santos, Nuno L Barbosa-Morais, Karine Serre","doi":"10.1158/2326-6066.CIR-24-0797","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0797","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 (hereafter termed myeloid cell treatment, MCT) reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and post-MCT revealed a transient antitumor TAM phenotype, present at 12h post-MCT, characterized by markers such as iNOS and CD38, which was replaced by TAMs co-expressing tumor-limiting and promoting features by 72h post-MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, ROS and TNF-α were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-15 Complex Enhances Agonistic Anti-CD40 + Anti-PDL1 by Correcting the T-bet to Tox Ratio in CD8+ T cells Infiltrating Pancreatic Ductal Adenocarcinoma.","authors":"Zoe C Schmiechen, Hezkiel A Nanda, Adam L Burrack, Grant H Hickok, Jonah Z Butler, Eduardo Cruz-Hinojoza, Nicholas J Maurice, Michael J Geuenich, Chengxin Yu, Alexander K Tsai, Cara-Lin Lonetree, Madeline A Ellefson, Audrey L Hilk, Brandon M Larsen, Ebony A Miller, Antonio B Rizzo, Kieran R Campbell, Steven S Shen, Ingunn M Stromnes","doi":"10.1158/2326-6066.CIR-24-0758","DOIUrl":"10.1158/2326-6066.CIR-24-0758","url":null,"abstract":"<p><p>Agonistic anti-CD40 with anti-PD-1 can elicit objective responses in a small number of patients with pancreatic ductal adenocarcinoma (PDA). Better understanding of their individual effects on the pancreatic tumor microenvironment will help inform new strategies to further improve outcomes. In this study, we map tumor-specific CD8+ T-cell differentiation following agonistic anti-CD40 and/or anti-PDL1 in PDA. Rare Tcf1+Slamf6+ tumor-specific CD8+ T cells are identified and likely seed memory precursors that transition into exhausted or effector T cells. In tumors, anti-PDL1 drove the clonal expansion of Gzmk+ progenitor exhausted CD8+ T cells, whereas anti-CD40 promoted CD4+ T-cell clonal expansion and accumulation of Tcf1+Slamf6+ CD8+ T cells. Cloning the most frequent intratumoral T-cell receptors revealed identical neoepitope specificity, yet the top T-cell receptors from anti-PDL1 ± anti-CD40 cohorts lacked tetramer binding, suggesting lower affinity. Anti-CD40 + anti-PDL1 markedly drove the clonal hyperexpansion of a unique exhausted T-cell subset in the spleen. Exhausted T cells were enriched for IL-2Rβ, and provision of IL-15 complex (IL-15C) mitigated systemic and intratumoral T-cell exhaustion when combined with anti-CD40 + anti-PDL1, resulting in enhanced antitumor effects, prolongation of animal survival, and resistance to orthotopic tumor rechallenge. Mechanistically, anti-CD40 + anti-PDL1 decreased Tox, whereas IL-15C + anti-CD40 + anti-PDL1 increased T-bet, thereby conferring a higher T-bet:Tox ratio in tumor-specific CD8+ T cells. Collectively, agonistic anti-CD40 + anti-PDL1 drove systemic and intratumoral CD8+ T-cell clonal expansion and acquisition of exhaustion features in a tissue-specific manner. Provision of IL-15C altered the trajectory of T-cell differentiation induced by immunotherapy, resulting in PDA eradication and long-lived antitumor memory T cells.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"847-866"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603968","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":"Cytoplasmic WEE1 Promotes Resistance to PD-1 Blockade Through Hyperactivation of the HSP90A/TCL1/AKT Signaling Axis in NANOGhigh Tumors.","authors":"Suyeon Kim, Hyo-Jung Lee, Seungho Lee, Jo Eun Chung, Se Jin Oh, Kwon-Ho Song, Eunho Cho, Min Kyu Son, Heeju Kwon, Seung-Jong Kim, Chaeleen Lee, Suhwan Chang, Tae Woo Kim","doi":"10.1158/2326-6066.CIR-24-0379","DOIUrl":"10.1158/2326-6066.CIR-24-0379","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has revolutionized the therapeutic landscape across various cancer types. However, the emergence of resistance to ICB therapy limits its clinical application. Therefore, it is necessary to better understand immune-resistance mechanisms that could be targeted by actionable drugs and important to identify predictive markers for selecting patients. In this study, by analyzing transcriptomic data from patients treated with PD-1 blockade and tumor models refractory to anti-PD-1 therapy, we identified WEE1 as a resistance factor conferring cancer stem cell-like properties as well as immune-refractory phenotypes to tumor cells. WEE1 is transcriptionally upregulated by stemness factor NANOG and predominantly localized in the cytoplasm, not the nucleus, following AKT-dependent S642 phosphorylation in immune-refractory tumor cells. Mechanistically, cytoplasmic WEE1 drove AKT hyperactivation via the HSP90A/TCL1A/AKT auto-amplification loop and upregulated the expression of refractory factors such as CYCLIN A for hyperproliferation and MCL-1 for resistance to T-cell killing. Of note, CXCL10 was downregulated, resulting in insufficient T-cell infiltration. The NANOG/WEE1/AKT axis was also conserved in various human cancers. Importantly, targeting WEE1 with a clinically relevant inhibitor sensitized NANOG+ immune-refractory tumors to ICB, reinvigorating antitumor immunity by disrupting the HSP90A/TCL1A/AKT loop. Thus, our findings demonstrate the oncogenic role of cytoplasmic WEE1 in immune-refractoriness and conferring cancer stem cell-like properties of tumor cells through AKT hyperactivation and provide a rationale for combining a WEE1 inhibitor to control anti-PD-1 therapy-refractory tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"912-930"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naturally Arising Memory-Phenotype CD4+ T Lymphocytes Give Rise to Multiple Helper Subsets to Contribute to Tumor Immunity while Inhibiting GVHD.","authors":"Ziying Yang, Jing Li, Hideaki Watanabe, Feng Gao, Akihisa Kawajiri, Keita Koinuma, Kosuke Sato, Yuko Okuyama, Shunichi Tayama, Yoichiro Iwakura, Naoto Ishii, Takeshi Kawabe","doi":"10.1158/2326-6066.CIR-24-0598","DOIUrl":"10.1158/2326-6066.CIR-24-0598","url":null,"abstract":"<p><p>Memory-phenotype (MP) CD4+ T lymphocytes spontaneously develop in steady state from peripheral naïve precursors in a manner dependent on self-antigen recognition. Although MP cells possess innate type 1 and 3 effector functions that can contribute to host defense and autoimmunity, their immunologic functions in tumor immunity and GVHD, which results from therapeutic bone marrow transplantation (BMT) against hematologic malignancies, remain unclear. In this study, we show that in mixed lymphocyte reactions, MP lymphocytes can generate Th1, Th17, and regulatory T (Treg) cell subsets, whereas naïve cells dominantly differentiate to Th1. Consistent with this, naïve lymphocytes mainly induce Th1 responses in the mouse EL4 model of malignant lymphoma and the B16 model of malignant melanoma, whereas MP cells efficiently give rise to Th1, Th17, and Treg cell subsets to exert mild, IFN-γ-dependent antitumor activities in vivo. Moreover, we demonstrate using a mouse model of BMT that MP cells more efficiently differentiate into Treg cells to partially suppress GVHD as compared to naïve T lymphocytes. Furthermore, our data suggest that when used as donor T lymphocytes in BMT in tumor-bearing mice, MP cells give rise to Th1, Th17, and Treg cells to generate antitumor responses without inducing GVHD. Together, these results identify MP cells as a unique T-cell population that has the potential to generate multiple Th subsets including Th1 and Treg cells, thereby contributing to tumor immunity while inhibiting the development of BMT-associated GVHD.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"897-911"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Delivery of Gasdermin E mRNA Promotes Antitumor Immunity via Creatine-Elicited Type I Interferon Signaling in Monocytes.","authors":"Hanjun Li, Jing Lu, Shudan Tan, Ting Jiang, Xin He, Wen Qiao, Cegui Hu, Sumiya Dalangood, Jinzhong Lin, Jun Gui","doi":"10.1158/2326-6066.CIR-24-0834","DOIUrl":"10.1158/2326-6066.CIR-24-0834","url":null,"abstract":"<p><p>Local immunotherapy stimulates immune responses against tumors while avoiding adverse effects associated with systemic administration. However, current strategies for tumor-targeted in situ immunotherapy are still limited. mRNA-based gene therapy represents a promising strategy. Gasdermin E (GSDME)-mediated pyroptosis is reported to exert antitumor immunity. In this study, we synthetized mRNA encoding GSDME encapsulated by lipid nanoparticles (LNP-Gsdme). In situ delivery of LNP-Gsdme through intratumoral injection suppressed tumor growth, boosted monocyte infiltration, and activated CD8+T cells. LNP-Gsdme induced immunogenic cell death in tumor cells, releasing creatine as a metabolic damage-associated molecular pattern. Creatine elicited the cGAMP-STING-type I IFN signaling pathway in monocytes and reprogrammed intratumoral monocytes toward an immunostimulatory phenotype, consequently potentiating CD8+ T cell-mediated antitumor immune responses. Furthermore, creatine supplementation enhanced the antitumor efficacy of LNP-Gsdme. Our study uncovers creatine as an important metabolic biomarker of pyroptosis-induced immunogenic cell death in tumors, providing new insights and a promising therapeutic approach for in vivo mRNA-based immunotherapies for cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"939-956"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination Therapy Approaches to Enhance the Efficacy of ERV-Targeting Vaccines in Cancer.","authors":"Maria Gracia-Hernandez, Maria Del Mar Maldonado, Jeffrey Schlom, Duane H Hamilton","doi":"10.1158/2326-6066.CIR-24-1192","DOIUrl":"10.1158/2326-6066.CIR-24-1192","url":null,"abstract":"<p><p>Endogenous retroviruses (ERV) are the genetic remnants of retroviruses in which proviral sequences integrated into germline cells of our ancestors. Although the vast majority of ERV sequences have accumulated mutations over the course of human evolution, some still contain open reading frames encoding full-length retroviral proteins. These sequences are typically epigenetically silenced in healthy adult human tissues. However, epigenetic dysregulation in cancer results in aberrant expression of ERVs in multiple cancer types. Therefore, ERVs represent a class of attractive therapeutic targets in cancer due to their immunogenicity and high expression in cancer cells compared with healthy tissues. In this review, we summarize the roles of ERVs in cancer and their immunogenicity, highlight the most recent advances in ERV-targeting strategies, discuss their challenges, and examine potential combination approaches that could further enhance the antitumor efficacy of ERV-targeting vaccines.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"792-803"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092904","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":"Anti-CTLA4 Therapy Leads to Early Expansion of a Peripheral Th17 Population and Induction of Th1 Cytokines.","authors":"Mari Nakazawa, Soren Charmsaz, Elsa Hallab, Mike Fang, Chester Kao, Madelena Brancati, Kabeer Munjal, Howard L Li, James M Leatherman, Ervin Griffin, Christopher J Thoburn, Evan J Lipson, Yasser Ged, Jean Hoffman-Censits, Marina Baretti, Laura Tang, Sanjay Bansal, Rachel Garonce-Hediger, Aditi Guha, G Scott Chandler, Rajat Mohindra, Elizabeth M Jaffee, Won Jin Ho, Mark Yarchoan","doi":"10.1158/2326-6066.CIR-24-1055","DOIUrl":"10.1158/2326-6066.CIR-24-1055","url":null,"abstract":"<p><p>The systemic immunologic effects of combining anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapy with PDL1 blockade remain incompletely characterized despite the widespread use of this combination in treating various solid tumors across multiple stages of disease. In this study, we investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PDL1 blockade, using blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors. We performed in-parallel analysis of peripheral blood mononuclear cells using cytometry by time of flight and plasma cytokines using Luminex immunoassay. Our study cohort included 104 patients: 54 received anti-PDL1 alone and 50 received anti-PDL1 in combination with anti-CTLA4. As compared with single-agent anti-PDL1, combination therapy was associated with a greater expansion of CD4+ Th cell subsets, including Th17 (adjusted P = 0.04) and regulatory T cells (adjusted P = 0.02), after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, examination of functional marker expression within the Th17 subset revealed an increase in the expression of the Th1-related transcription factor TBET (P = 0.003). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines (P = 0.002) in recipients of combination anti-PDL1 and anti-CTLA4, particularly the IFNγ-inducible cytokines MIG (adjusted P = 0.05) and IP-10 (adjusted P = 0.05). Our results confirm prior reports that anti-CTLA4 therapy is associated with the augmentation of Th17 cell subsets, and they also show that anti-CTLA4 may reshape CD4+ T-cell responses through Th17-to-Th1 plasticity, revealing a potential mechanism for enhanced antitumor immunity with broader implications for immune modulation in immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"836-846"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12136996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718112","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":"CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.","authors":"Divanshu Shukla, Khatuna Gabunia, Shannon E McGettigan, Prachi R Patel, Shannon Christensen, Ting-Jia Fan, Decheng Song, Yanping Luo, Yanling Wang, Huaishan Wang, Regina M Young, Carl H June, John Scholler, James L Riley","doi":"10.1158/2326-6066.CIR-24-1347","DOIUrl":"10.1158/2326-6066.CIR-24-1347","url":null,"abstract":"<p><p>Patients can develop human anti-mouse immune responses against CD19-specific chimeric antigen receptor (CAR) T cells due to the use of a murine CD19-specific single-chain variable fragment to redirect T cells. We screened a yeast display library to identify an array of fully human CD19 single-chain variable fragment binders and performed a series of studies to select the most promising fully human CAR. We observed significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T-cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this initial analysis, CAR T cells using two binders (42 and 52) were selected for additional studies. Although CAR T cells using both binders controlled tumor growth well in vivo, we advanced a CAR construct using binder 42 for more advanced preclinical testing because of its greater similarity to binders based on the antibody FMC63, which is the murine antibody underlying four FDA-approved CD19-specific CAR T-cell therapies, and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 and with ∼40-fold lower affinity. CARs using binder 42 were non-inferior to those using the FMC63 binder in a mouse model of acute lymphoblastic leukemia, indicating that CAR T cells using binder 42 should be considered for clinical use.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"867-880"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981295","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":"Memory-like Natural Killer Cell and CD19 Antibody-Based Immunotherapy in Combination with Tyrosine Kinase Inhibition Has Antitumor Effects against Ph(-like) Acute Lymphoblastic Leukemia.","authors":"Zoya Eskandarian, Richard Hauch, Sabrina Schuster, Dorothee Winterberg, Hjördis Grabellus, Carlotta Imelmann, Anna-Lena Heitmann, Marlene Goos, Khadija Rudloff, Julia Strauss, Gerrit Wolters-Eisfeld, Peter Nollau, Katja Klausz, Ulrich Schüller, Matthias Peipp, Michael Spohn, Martin A Horstmann","doi":"10.1158/2326-6066.CIR-24-0746","DOIUrl":"10.1158/2326-6066.CIR-24-0746","url":null,"abstract":"<p><p>Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a molecularly distinct tyrosine kinase-driven cancer that has a high relapse rate and poor response toward combinatorial chemotherapy. Tyrosine kinase inhibitors (TKI) in the clinic improve the survival of patients with Ph-like ALL. Engineered antibody and cell-based immunotherapies can advance treatment for this genetic subtype of ALL. Allogeneic memory-like natural killer (ML-NK) cells have been used to treat leukemia and have shown a low risk of graft-versus-host reaction, which may be combined with leukemia epitope-targeting antibodies. However, mutation or pathway-directed TKI of Ph-like ALL can interfere with memory function and antibody-dependent NK cell-mediated cytotoxicity (ADCC). In this study, we explored the potential of ML-NK cells and Fc-enhanced CD19-ADCC in combination with TKI directed against kinase-driven leukemia models, including patient-derived xenografted Ph-like ALL. We demonstrate that receptor cross-linking in coculture with K562 feeder cells generated a more robust memory-like state of NK cells than coactivation with soluble IL-12, IL-15, and IL-18, as determined by genomic and functional studies. After receptor cross-linking and subsequent ILs preactivation, the optimized ML-NK cells showed enhanced antileukemic effector functions, which could compensate for exhausted B-cell precursor leukemia-infiltrating primary NK cells. TKI differentially affected multiple features of NK cell biology including viability, expansion, metabolism, receptor repertoire, and cytotoxicity. ADCC was maintained upon exposure to specific Abelson (ABL) or Janus kinase (JAK) inhibitors, in contrast to the multitarget TKI dasatinib impeding spleen tyrosine kinase-dependent ADCC. In conclusion, optimized ML-NK cell and CD19 antibody-based immunotherapy combined with carefully selected TKI demonstrates significant in vitro treatment efficacy in kinase-driven leukemia.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"881-896"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762947","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}