Cancer immunology research最新文献

{"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":"https://doi.org/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 PDA tumor microenvironment will help inform new strategies to further improve outcomes. Herein, we map tumor-specific CD8+ T-cell differentiation following agonistic anti-CD40 and/or anti-PDL1 in PDA. Rare Tcf1+Slamf6+ CD8+ T cells (TSTEM) are shown to seed memory precursors that transition into a continuum of exhausted and 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 CD8+ TTSTEM. Cloning the most frequent intratumoral T-cell receptors (TCRs) revealed identical neoepitope specificity, yet the top TCRs 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 (TEX) subset in spleen. TEX were enriched for IL2R, 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, while anti-CD40 + anti-PDL1 mitigated Tox, 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 and anti-PDL1 drove systemic and intratumoral CD8+ T-cell clonal expansion and acquisition of exhaustion features. 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cGAS mRNA-based Immune Agonist Promotes Vaccine Responses and Antitumor Immunity.","authors":"Yali Qu, Zhibin Li, Jiahao Yin, He Huang, Jialu Ma, Zhelin Jiang, Qian Zhou, Ying Tang, Yuting Li, Minpeng Huang, Zhutian Zeng, Ao Guo, Fang Fang, Yanqiong Shen, Ruibo Zhao, Yucai Wang, Daxing Gao","doi":"10.1158/2326-6066.CIR-24-0804","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0804","url":null,"abstract":"<p><p>mRNA vaccines are recognized as potent tools for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. Here, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNPs) to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained STING-mediated interferon (IFN) response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment and antigen presentation by antigen-presenting cells (APCs) both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination has shown a robust adjuvant effect, amplifying the potency of mRNA and protein vaccines by inducing strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted synergistic antitumor effects with IFNγ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS-mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603937","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":"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":"https://doi.org/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. Here, 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 (CSC)-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 andupregulated 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 CSC-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":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","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":"Cytotoxic chemotherapy in a 3D microfluidic device induces dendritic cell recruitment and trogocytosis of cancer cells.","authors":"Dohyun Park, Inae Park, Bohwa Han, Yujin Baek, Dowon Moon, Noo Li Jeon, Junsang Doh","doi":"10.1158/2326-6066.CIR-24-0263","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0263","url":null,"abstract":"<p><p>Cytotoxic chemotherapy that kills cancer cells can also elicit anti-tumor immune responses. Therefore, understanding the immunogenic context of cytotoxic chemotherapy can improve combination immunotherapies. In this study, we sought to improve our understanding about dendritic cell (DC) dynamics in cytotoxic chemotherapy-treated tumor tissues by developing 3D microfluidic devices that enable high-resolution visualization of cellular dynamics. Specifically, microfluidic chips mimicking 3D tumor tissues were fabricated and used. Collagen gel blocks encapsulating cancer cells in microfluidics were treated with various concentrations of oxaliplatin (OXP). Then, DCs were attached on the side of the collagen gel blocks, and migration of DCs within the 3D gels was quantitatively analyzed. Interactions between OXP-treated cancer cells and DCs were observed by high-resolution time-lapse imaging. Active infiltration of DCs was predominantly observed when OXP was administrated, indicating OXP-treated cancer cells release factors promoting DC motility. The highest frequency of DC recruitment was detected at a moderate OXP concentration, suggesting that optimizing the dosage of cytotoxic chemotherapy is crucial in order to improve immunogenic cell death (ICD). High-resolution video microscopy revealed that DCs employ trogocytosis to disassemble dying/dead cancer cells and acquire antigens, as opposed to phagocytosing the entire cancer cells. Microfluidic chip-based observations may provide new insights for the design of new therapeutic strategies to combine chemotherapy and immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603966","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":"Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy.","authors":"Jiazheng Sun, Pin Wang, Ziying Yi, Yushen Wu, Yuxian Wei, Huiying Fang, Daqiang Song, Yuru Chen, Huimin Du, Jing Huang, Qin Li, Dejuan Yang, Guosheng Ren, Hongzhong Li","doi":"10.1158/2326-6066.CIR-24-0484","DOIUrl":"10.1158/2326-6066.CIR-24-0484","url":null,"abstract":"<p><p>The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated the Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"400-416"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738521","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":"Profiling Multiple CD8+ T-cell Functional Dimensions Enhances Breast Cancer Immune Assessment.","authors":"Zhuozhi Liang, Shunrong Li, Zhilong Pan, Yuanqiang Duan, Qian Ouyang, Liling Zhu, Erwei Song, Kai Chen","doi":"10.1158/2326-6066.CIR-24-0235","DOIUrl":"10.1158/2326-6066.CIR-24-0235","url":null,"abstract":"<p><p>CD8+ T-cell abundance is insufficient to assess antitumor immunity and shows poor performance in predicting breast cancer prognosis and immunotherapy response, presumably owing to the complexity of CD8+ T-cell functionalities. Although single-cell RNA sequencing can dissect the multifaceted functions of CD8+ T cells for better immune assessment, its clinical application is limited. In this study, we developed bulk RNA sequencing-based FuncDimen models from integrative analysis of single-cell RNA sequencing and matched bulk RNA sequencing data to evaluate CD8+ T-cell functionalities across five dimensions: tumor reactivity, cytotoxicity, IFNγ secretion, proliferation, and apoptosis. The FuncDimen models quantifying different functional dimensions of CD8+ T cells were validated in our breast cancer cohort and external databases using immunofluorescence and imaging mass cytometry. We calculated the FuncAggre score by weighted aggregation of all five FuncDimen models to encapsulate the overall antitumor immunity. In our breast cancer cohort and external databases, the FuncAggre score demonstrated superior predictive performance for breast cancer prognosis (time-dependent AUC: 0.56-0.70) and immunotherapy response (AUC: 0.71-0.83) over other immune biomarkers, regardless of the breast cancer molecular subtype. Together, the FuncDimen models offer a refined assessment of antitumor immunity mediated by CD8+ T cells in the clinic, enhancing prognostic prediction and aiding personalized immunotherapy in breast cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"337-352"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881448","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":"The C5a/C5aR1 Axis Promotes Migration of Tolerogenic Dendritic Cells to Lymph Nodes, Impairing the Anticancer Immune Response.","authors":"Yaiza Senent, Ana Remírez, David Repáraz, Diana Llopiz, Daiana P Celias, Cristina Sainz, Rodrigo Entrialgo-Cadierno, Lucia Suarez, Ana Rouzaut, Diego Alignani, Beatriz Tavira, John D Lambris, Trent M Woodruff, Carlos E de Andrea, Brian Ruffell, Pablo Sarobe, Daniel Ajona, Ruben Pio","doi":"10.1158/2326-6066.CIR-24-0250","DOIUrl":"10.1158/2326-6066.CIR-24-0250","url":null,"abstract":"<p><p>The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment and promotes tumor progression remain unclear. In this study, we investigated the expression and function of complement C5a receptor 1 (C5aR1) in human and mouse cancer-associated dendritic cells (DC). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared with DCs from the blood or spleen. C5aR1 expression was restricted to type 2 conventional DCs and monocyte-derived DCs, which displayed a tolerogenic phenotype capable of inhibiting T-cell activation and promoting tumor growth. C5aR1 engagement in DCs drove their migration from tumors to tumor-draining lymph nodes, where C5a levels were higher. We used this knowledge to optimize an anticancer therapy aimed at enhancing DC activity. In three syngeneic tumor models, C5aR1 inhibition significantly enhanced the efficacy of poly I:C, a Toll-like receptor 3 agonist, in combination with PD-1/PD-L1 blockade. The contribution of C5aR1 inhibition to the antitumor activity of the combination treatment relied on type 1 conventional DCs and antigen-specific CD8+ T cells, required lymphocyte egress from secondary lymphoid organs, and was associated with an increase in IFNγ signaling. In conclusion, our study highlights the importance of the C5a/C5aR1 axis in the biology of cancer-associated DCs and provides compelling evidence for the therapeutic potential of modulating the complement system to enhance DC-mediated immune responses against tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"384-399"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812115","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":"Mathematical Modeling Predicts Optimal Immune Checkpoint Inhibitor and Radiotherapy Combinations and Timing of Administration.","authors":"Shunsuke A Sakai, Koichi Saeki, SungGi Chi, Yamato Hamaya, Junyan Du, Masaki Nakamura, Hidehiro Hojo, Takashi Kojima, Yoshiaki Nakamura, Hideaki Bando, Motohiro Kojima, Ayako Suzuki, Yutaka Suzuki, Tetsuo Akimoto, Katsuya Tsuchihara, Hiroshi Haeno, Riu Yamashita, Shun-Ichiro Kageyama","doi":"10.1158/2326-6066.CIR-24-0610","DOIUrl":"10.1158/2326-6066.CIR-24-0610","url":null,"abstract":"<p><p>Radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) therapy has attracted substantial attention due to its potential to improve outcomes for patients with several types of cancer. However, the optimal administration timepoints and drug combinations remain unclear because the mechanisms underlying RT-induced changes in immune checkpoint molecule expression and interaction with their ligand(s) remain unclear. In this study, we demonstrated the dynamics of lymphocyte-mediated molecular interactions in tissue samples from patients with esophageal cancer throughout RT schedules. Single-cell RNA sequencing and spatial transcriptomic analyses were performed to investigate the dynamics of these interactions. The biological signal in lymphocytes transitioned from innate to adaptive immune reaction, with increases in ligand-receptor interactions, such as PD-1-PD-L1, CTLA4-CD80/86, and TIGIT-PVR interactions. A mathematical model was constructed to predict the efficacy of five types of ICIs when administered at four different timepoints. The model suggested that concurrent anti-PD-1/PD-L1 therapy or concurrent/adjuvant anti-CTLA4/TIGIT therapy would exert a maximal effect with RT. This study provides rationale for clinical trials of RT combined with defined ICI therapy, and these findings will support future studies to search for more effective targets and timing of therapy administration.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"353-364"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812114","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":"A Sampling of Highlights from the Literature.","authors":"","doi":"10.1158/2326-6066.CIR-13-3-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-13-3-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 3","pages":"309"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540232","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":"NI-3201 Is a Bispecific Antibody Mediating PD-L1-Dependent CD28 Co-stimulation on T Cells for Enhanced Tumor Control.","authors":"Sara Majocchi, Pauline Lloveras, Lise Nouveau, Margaux Legrand, Alizee Viandier, Pauline Malinge, Maud Charreton, Cecile Raymond, Emily A Pace, Bjorn L Millard, L Anders Svensson, Vinardas Kelpšas, Nadia Anceriz, Susana Salgado-Pires, Bruno Daubeuf, Giovanni Magistrelli, Franck Gueneau, Valéry Moine, Krzysztof Masternak, Limin Shang, Nicolas Fischer, Walter G Ferlin","doi":"10.1158/2326-6066.CIR-24-0298","DOIUrl":"10.1158/2326-6066.CIR-24-0298","url":null,"abstract":"<p><p>Despite advances in cancer immunotherapy, such as targeting the PD-1/PD-L1 axis, a substantial number of patients harbor tumors that are resistant or relapse. Selective engagement of T-cell co-stimulatory molecules with bispecific antibodies may offer novel therapeutic options by enhancing signal 1-driven activation occurring via T-cell receptor engagement. In this study, we report the development and preclinical characterization of NI-3201, a PD-L1×CD28 bispecific antibody generated on the κλ-body platform that was designed to promote T-cell activity and antitumor function through a dual mechanism of action. We confirmed that NI-3201 blocks the PD-L1/PD-1 immune checkpoint pathway and conditionally provides T-cell co-stimulation via CD28 (signal 2) when engaging PD-L1+ tumors or immune cells. In systems with signal 1-primed T cells, NI-3201 enhanced potent effector functionality: in vitro through antigen-specific recall assays with cytomegalovirus-specific T cells and in vivo by inducing tumor regression and immunologic memory in tumor-associated antigen-expressing MC38 syngeneic mouse models. When T-cell engagers were used to provide synthetic signal 1, the combination with NI-3201 resulted in synergistic T cell-dependent cytotoxicity and potent antitumor activity in two humanized mouse tumor models. Nonhuman primate safety assessments showed favorable tolerability and pharmacokinetics at pharmacologically active doses. Quantitative systems pharmacology modeling predicted that NI-3201 exposure results in antitumor activity in patients, but this remains to be investigated. Overall, this study suggests that by combining PD-L1 blockade with safe and effective CD28 co-stimulation, NI-3201 has the potential to improve cancer immunotherapy outcomes, and the clinical development of NI-3201 for PD-L1+ solid tumors is planned.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"365-383"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930623","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}