Cancer immunology research最新文献

{"title":"A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer.","authors":"Shee Kwan Phung, Nicholas A Zorko, Yvette Soignier, Rhett L Waller, Madison Shackelford, Joshua T Walker, Trygve D Nelson, Carly Selleck, Laura E Bendzick, Laura E Kotz, Quinlan M Kile, Asha J Bozicevich, Sarah E Miller, Melissa Khaw, Mihir Shetty, Peter Hinderlie, Michael Ehrhardt, Yingming Li, Xianghua Luo, Scott M Dehm, Emmanuel S Antonarakis, Philippa R Kennedy, Jeffrey S Miller, Martin Felices","doi":"10.1158/2326-6066.CIR-24-0273","DOIUrl":"10.1158/2326-6066.CIR-24-0273","url":null,"abstract":"<p><p>NK cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with coactivation may enhance NK cell function in mCRPC. We describe a tri-specific killer engager (TriKE) construct that engages with the activating receptor CD16 on NK cells and prostate-specific membrane antigen (PSMA) on mCRPC cells and has an IL15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation, and cytokine production of NK cells derived from healthy donors or patients with prostate cancer. Bystander killing of PSMA-negative tumor cells was also achieved with PSMA TriKE treatment when cocultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment, NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or myeloid-derived suppressor cells maintained their potent function whereas IL15-treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared with IL15-treated and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their antitumor potential in prostate cancer, especially in the setting of a hostile tumor microenvironment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"258-272"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638431","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":"Tertiary lymphoid structures are associated with enhanced macrophage activation and immune checkpoint expression, and predict outcome in cervical cancer.","authors":"Laurent Gorvel, Marylou Panouillot, Marie-Sarah Rouvière, Emilien Billon, Stéphane Fattori, Jumaporn Sonongbua, Nicolas Boucherit, Amira Ben Amara, Olivia Quilichini, Samuel Granjeaud, Clara Degos, Jacques A Nunès, Xavier Carcopino, Eric Lambaudie, Anne-Sophie Chrétien, Renaud Sabatier, Marie-Caroline Dieu-Nosjean, Daniel Olive","doi":"10.1158/2326-6066.CIR-24-0979","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0979","url":null,"abstract":"<p><p>Cervical tumors are usually treated using surgery, chemotherapy, and radiotherapy, and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in cancer patients. We evaluated the cervical tumor immune microenvironment, specifically focusing on TLS, using combined high-throughput phenotyping, soluble factor concentration dosage in the TME and spatial interaction analyses. We found that TLS presence was associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DCs). Furthermore, this myeloid cell activation was associated with expression of immune checkpoints, such as PD-L1 and CD40, and proximity of activated conventional type 2 DCs (DC2) to CD8+ T cells, indicating better immune interactions and tumor control. Finally, we associated TLS presence, greater B cell density, and activated DC density with improved progression-free survival, substantiating TLS presence as a potential prognostic marker. Our results provide evidence that TLS presence denotes cell activation and immunotherapy target expression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070739","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":"A bifunctional antibody targeting PD-1 and TGF-β signaling has antitumor activity in combination with radiotherapy and attenuates radiation-induced lung injury.","authors":"Sheng Wang, Duo Xu, Yuan Wang, Yuehua Zhou, Lingyan Xiao, Fang Li, Jingyao Tu, Wan Qin, Sidan Tian, Bolong Zheng, Yihua Wang, Xiang-Lin Yuan, Yuanhui Liu, Bo Liu","doi":"10.1158/2326-6066.CIR-23-0903","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-23-0903","url":null,"abstract":"<p><p>Radio-immunotherapy has antitumor activity but also causes toxicity, which limits its clinical application. JS-201 is a dual antibody targeting PD-1 and TGF-β signaling. We investigated the antitumour effect of JS-201 combined with radiotherapy and the effect on radiation-induced lung injury (RILI). Different tumor models were established to detect the antitumor effects of the combination of JS-201 and RT, and RILI models were established to observe the effects of JS-201. Transcriptome sequencing showed that JS-201 optimized the TME by inhibiting extracellular matrix formation and angiogenesis. Combining JS-201 with radiotherapy further increased the inflammatory response and immune infiltration and showed great abscopal effects in LLC-luc models. Single-cell sequencing demonstrated that JS-201 reduced fibroblast proliferation by inhibiting the TGF-β/Smad pathway and the release of neutrophil extracellular traps mediated by ROS, thereby relieving radiation-induced pulmonary fibrosis. In conclusion, the JS-201 and radiotherapy combination enhances antitumor effects while mitigating acute and chronic RILI, and it may have potential for translational investigation as a cancer treatment strategy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058266","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":"Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer.","authors":"Matthew D Galsky, Mark Kockx, Juliette Roels, Roos Van Elzen, Xiangnan Guan, Kobe Yuen, Deepali Rishipathak, Jonathan F Anker, Sacha Gnjatic, Sudeh Izadmehr, Shomyesh Sanjabi, Robert J Johnston, Maureen Peterson, Hartmut Koeppen, Justin M David, Saurabh Gupta, Aristotelis Bamias, Jose Angel Arranz, Eiji Kikuchi, Maria De Santis, Ian D Davis, Patrick Williams, Sandrine Bernhard, Ira Mellman, Enrique Grande, Romain Banchereau, Sanjeev Mariathasan","doi":"10.1158/2326-6066.CIR-24-0649","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0649","url":null,"abstract":"<p><p>Testing for PD-L1 expression by immunohistochemistry (IHC) is used to predict immune checkpoint blockade (ICB) benefit but has performed inconsistently in urothelial cancer (UC) clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on UC samples using the SP142 and 22C3 assays from the phase 3 IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays (PD-L1 double positive; PD-L1DP), PD-L1 positive by the SP142 assay only (SP142 single positive; SP142SP), PD-L1 positive by the 22C3 assay only (22C3 single positive; 22C3SP), and PD-L1 negative by both assays double negative (PD-L1 double negative; PD-L1DN). PD-L1DP and SP142SP UCs were associated with more favorable ICB outcomes and increased dendritic-cell (DC) infiltration. SP142 PD-L1 staining co-localized with DC-LAMP, a DC marker, while 22C3 staining was more diffuse. 22C3SP UCs, associated with worse outcomes, were enriched in tumor cell-dominant PD-L1 expression. Multiplex IHC in an independent ICB-treated cohort confirmed that tumor cell-dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1-expressing DCs, key to orchestrating antitumor immunity, while tumor cell-dominant PD-L1 expression, which underlies a subset of \"PD-L1 positive\" specimens, is associated with poor ICB outcomes.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032314","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":"PRDM1 is a key regulator of the natural killer T-cell central memory program and effector function.","authors":"Gengwen Tian, Gabriel A Barragán, Hangjin Yu, Claudia Martinez-Amador, Akshaya Adaikkalavan, Xavier Rios, Linjie Guo, Janice M Drabek, Osmay Pardias, Xin Xu, Antonino Montalbano, Chunchao Zhang, Yanchuan Li, Amy N Courtney, Erica J Di Pierro, Leonid S Metelitsa","doi":"10.1158/2326-6066.CIR-24-0259","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0259","url":null,"abstract":"<p><p>Natural killer T cells (NKTs) are a promising platform for cancer immunotherapy, but few genes involved in regulation of NKT therapeutic activity have been identified. To find regulators of NKT functional fitness, we developed a CRISPR/Cas9-based mutagenesis screen that employs a guide RNA (gRNA) library targeting 1,118 immune-related genes. Unmodified NKTs and NKTs expressing a GD2-specific chimeric antigen receptor (GD2.CAR) were transduced with the gRNA library and exposed to CD1d+ leukemia or CD1d-GD2+ neuroblastoma cells, respectively, over six challenge cycles in vitro. Quantification of gRNA abundance revealed enrichment of PRDM1-specific gRNAs in both NKTs and GD2.CAR NKTs, a result that was validated through targeted PRDM1 knockout. Transcriptional, phenotypic, and functional analyses demonstrated that CAR NKTs with PRDM1 knockout underwent central memory-like differentiation and resisted exhaustion. However, these cells downregulated the cytotoxic mediator granzyme B and showed reduced in vitro cytotoxicity and only moderate in vivo antitumor activity in a xenogeneic neuroblastoma model. In contrast, shRNA-mediated PRDM1 knockdown preserved effector function while promoting central memory differentiation, resulting in GD2.CAR NKTs with potent in vivo antitumor activity. Thus, we have identified PRDM1 as a regulator of NKT memory differentiation and effector function that can be exploited to improve the efficacy of NKT-based cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000907","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":"PKCδ germline variants and genetic deletion in mice augment antitumor immunity through regulation of myeloid cells.","authors":"Kyle R Cron, Ayelet Sivan, Keston Aquino-Michaels, Andrea Ziblat, Emily F Higgs, Randy F Sweis, Ruxandra Tonea, Seoho Lee, Thomas F Gajewski","doi":"10.1158/2326-6066.CIR-23-0999","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-23-0999","url":null,"abstract":"<p><p>Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified PKCδ as a candidate. Genetic deletion of PKCδ in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of PKCδ in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ KO-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977624","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 detection of individual classical MHC-I gene products in cancer.","authors":"Paula I Gonzalez-Ericsson, Susan R Opalenik, Violeta Sanchez, Amy Palubinsky, Ann Hanna, Xiaopeng Sun, Andres A Ocampo, Guadalupe Garcia, Leonel Maldonado, Zaida Morante, Tatiana Vidaurre, Guillermo Valencia, Henry L Gomez, Melinda E Sanders, Laura C Kennedy, Elizabeth Phillips, Justin M Balko","doi":"10.1158/2326-6066.CIR-24-1003","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1003","url":null,"abstract":"<p><p>Tumor-specific HLA class I expression is required for cytotoxic T-cell elimination of cancer cells expressing tumor-associated or neo-antigens. Cancers downregulate antigen presentation to avoid adaptive immunity. The highly polymorphic nature of the genes encoding these proteins, coupled with quaternary-structure changes after formalin fixation, complicate detection by immunohistochemistry. In this study we determined recognition of 16 specific HLA-A, B and C alleles by 15 antibodies commercially available for immunohistochemical use, identifying and validating pan and specific HLA-A, B, and C antibodies, providing a validated method that can be applied to investigate HLA-A, B and C molecule-specific loss in cancer. We applied this approach to a series of breast cancers as a proof of utility, identifying differential HLA-A, B and C loss, with a higher incidence of HLA-A and B loss in hormone-driven breast cancers, HLA-B loss in HER2+ cancers, and an equal loss of all three molecules in triple-negative disease. Additionally, we found that at the protein level, HLA-A and B loss were early events prevalent in premalignant lesions, while HLA-C loss was less common throughout tumor evolution. Effective response to immunotherapies such as checkpoint inhibitors and MHC-I-targeted cancer vaccines, which hinge on the carriage of specific allele groups, require MHC-I expression on tumor cells. These findings have implications for the success of checkpoint inhibitors and vaccine strategies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969016","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":"Preclinical Development of T Cells Engineered to Express a T-Cell Antigen Coupler Targeting Claudin 18.2-Positive Solid Tumors.","authors":"Stacey X Xu, Ling Wang, Philbert Ip, Ritu R Randhawa, Tania Benatar, Suzanna L Prosser, Prabha Lal, Alima Naim Khan, Thanyashanthi Nitya-Nootan, Gargi Thakor, Heather MacGregor, Danielle L Hayes, Andrea Vucicevic, Princy Mathew, Sadhak Sengupta, Christopher W Helsen, Andreas G Bader","doi":"10.1158/2326-6066.CIR-24-0138","DOIUrl":"10.1158/2326-6066.CIR-24-0138","url":null,"abstract":"<p><p>The T-cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T-cell receptor complex in the absence of tonic signaling. Previous data demonstrate that the TAC affords T cells with the ability to induce durable and safe antitumor responses in preclinical models of hematologic and solid tumors. In this study, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T-cell therapy, TAC01-CLDN18.2, in preparation for a phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and were positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting antitumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"35-46"},"PeriodicalIF":8.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11712040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458700","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":"Alternate MHC I Antigen Presentation Pathways Allow CD8+ T-cell Recognition and Killing of Cancer Cells in the Absence of β2M or TAP.","authors":"Freidrich M Cruz, Laura A A Orellano, Amanda Chan, Kenneth L Rock","doi":"10.1158/2326-6066.CIR-24-0320","DOIUrl":"10.1158/2326-6066.CIR-24-0320","url":null,"abstract":"<p><p>MHC I antigen presentation allows CD8+ T cells to detect and eliminate cancerous or virally infected cells. The MHC I pathway is not essential for cell growth and viability, so cancers and viruses can evade control by CD8+ T cells by inactivating antigen presentation. In cancers, two common ways for this evasion are the loss of either the MHC I light chain [β2 microglobulin (β2M)] or the transporter-associated with antigen processing (TAP). β2M-null cells are generally thought to lack the MHC I pathway because the MHC I heavy chain by itself lacks the proper conformation for peptide display. TAP-null cells are thought to have severely defective MHC I antigen presentation because they are incapable of supplying peptides from the cytosol to MHC I molecules in the endoplasmic reticulum (ER). However, we have found that highly reactive memory CD8+ T cells could still recognize cells that completely lacked β2M or TAP. This was at least in part because in TAP-null cells, the Sec62 component of the Sec61 translocon supported the transfer of cytosolic peptides into the ER. In β2M-negative cells, free MHC I heavy chains were able to bind peptides and assume a conformation that was sufficiently recognized by CD8+ T cells. This process required ER chaperones and the peptide-loading complex. We found that these mechanisms supported antigen presentation at a level that was sufficient for memory CD8+ T cells to kill melanoma cells both in vitro and in tumor-bearing mice. The implications for tumor immunotherapy are discussed.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"98-108"},"PeriodicalIF":8.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562642","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":"Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by Long-term Glutamine Blockade in Bladder Cancer.","authors":"Guofeng Ma, Huiqing Jia, Zhiqiang Li, Xiangyan Zhang, Liping Wang, Zhilei Zhang, Yujing Xiao, Zhijuan Liang, Dan Li, Yuanbin Chen, Xintao Tian, Yonghua Wang, Ye Liang, Haitao Niu","doi":"10.1158/2326-6066.CIR-24-0039","DOIUrl":"10.1158/2326-6066.CIR-24-0039","url":null,"abstract":"<p><p>Glutamine is a major energy source for tumor cells, and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. In this study, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) inhibited the growth of bladder cancer cells in vitro in several ways. In addition, we observed inhibition of tumor growth in bladder cancer-bearing mice by using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade upregulated PD-L1 expression in bladder cancer cells by accumulating reactive oxygen species, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combination treatment of JHU083 and gefitinib reversed the upregulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"66-83"},"PeriodicalIF":8.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521079","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}