{"title":"C5a/C5aR pathway blocking promoted CuS-mediated cancer therapy effect by inhibiting cuproptosis resistance.","authors":"Hong Yang, Boshao Deng, Xiao Han, Lulu Wang, Jing Zhao, Yunpei Zhao, Zihan Sun, Siyi Wang, Guokang Liu, Yuzhang Wu, Jian Chen","doi":"10.1136/jitc-2025-011472","DOIUrl":"10.1136/jitc-2025-011472","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the most diagnosed malignancy and a leading cause of cancer-related deaths among women globally. Cuproptosis plays a significant role in tumor progression and therapeutic response. Increasing studies suggest that targeting cuproptosis presents a promising strategy for cancer therapy, such as through the development of copper nanoparticles as therapeutic agents. However, resistance to cuproptosis has emerged as a critical hallmark of cancer. Therefore, it is essential to further investigate the mechanisms underlying cuproptosis resistance to enhance its therapy effect.</p><p><strong>Methods: </strong>The relationship between breast cancer progression and the C5a/C5aR pathway or cuproptosis was determined by single-cell RNA sequencing analyses, RNA-sequence analyses, bioinformatic analyses, survival analyses and immunohistochemistry. The antitumor effects of CuS nanoparticles and C5a receptor antagonists (C5aRA) were assessed by in vitro and in vivo strategies including cell counting kit-8, colony formation assay, relative reactive oxygen species level assay, western blots, real-time quantitative PCR, immunohistochemistry, immunofluorescence assay, flow cytometry and the xenograft mice models. Complement system activation by CuS nanoparticles was tested by ELISA.</p><p><strong>Results: </strong>Our results indicated that activation of the C5a/C5aR pathway contributes to cuproptosis resistance by upregulating ATP7B expression via the Wnt/β-catenin pathway. Consequently, combining CuS nanoparticles with lazer treatment and C5aRA markedly enhanced the antitumor efficacy of CuS nanoparticles by overcoming cuproptosis resistance, leading to a synergistic effect in cancer therapy that included cuproptosis-targeting therapy, immunotherapy, and photothermal therapy.</p><p><strong>Conclusions: </strong>This study reports, for the first time, proved C5a/C5aR pathway-mediated cuproptosis resistance in cancer cells, and combining CuS nanoparticles and C5aRA offers a superior and novel therapeutic strategy for cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247939","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}
Christopher R Cabanski, EnJun Yang, Mark D Stewart, Jeff D Allen, John E Connolly, Ute Dugan, Philip D Greenberg, Crystal L Mackall, Carl H June, Alexander Marson, Marcela V Maus, Antoni Ribas
{"title":"Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.","authors":"Christopher R Cabanski, EnJun Yang, Mark D Stewart, Jeff D Allen, John E Connolly, Ute Dugan, Philip D Greenberg, Crystal L Mackall, Carl H June, Alexander Marson, Marcela V Maus, Antoni Ribas","doi":"10.1136/jitc-2024-011301","DOIUrl":"10.1136/jitc-2024-011301","url":null,"abstract":"<p><p>Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the \"Unlocking Complex Cell-based Gene Therapies\" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247944","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-T cell therapy in older adults with relapsed/refractory LBCL: benefits and challenges.","authors":"Leyla Shune, Matthew J Frigault, Peter A Riedell","doi":"10.1136/jitc-2024-009793","DOIUrl":"10.1136/jitc-2024-009793","url":null,"abstract":"<p><p>Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor prognosis with a high unmet need for efficacious treatment options. Most patients with r/r large B-cell lymphoma (LBCL) are elderly, which adds to the complexity of choosing the appropriate and effective therapy in these patients. Recently approved therapies, such as CD19-targeted chimeric antigen receptor-T cell therapy, have shown improvements in the outcomes of patients with r/r DLBCL. Several real-world studies also support the use of these newer therapies in elderly patients. However, given the frailty, variability in the risk factors in each elderly patient, and the increased susceptibility for adverse events, a comprehensive geriatric assessment and a multidisciplinary approach could be helpful in guiding the management and treatment choices for these vulnerable patients. Individualized care can aid in giving elderly patients with r/r LBCL the best possible outcome with their chosen treatment regimen.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247940","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}
Henning Zelba, Borong Shao, Armin Rabsteyn, Annekathrin Reinhardt, Carsten Greve, Lisa Oenning, Simone Kayser, Christina Kyzirakos, Pauline Latzer, Tabea Riedlinger, Oliver Bartsch, Julian Wünsche, Johannes Harter, Magdalena Feldhahn, Yannick Bantel, Janina Johänning, Jiri Ködding, Dirk Hadaschik, Martin Schulze, Florian Battke, Olga Maksimovic, Veit Scheble, Alexandra M Miller, Michael Castro, Deborah T Blumenthal, Martin Glas, David Reardon, Saskia Biskup
{"title":"In-depth characterization of vaccine-induced neoantigen-specific T cells in patients with IDH1-mutant glioma undergoing personalized peptide vaccination.","authors":"Henning Zelba, Borong Shao, Armin Rabsteyn, Annekathrin Reinhardt, Carsten Greve, Lisa Oenning, Simone Kayser, Christina Kyzirakos, Pauline Latzer, Tabea Riedlinger, Oliver Bartsch, Julian Wünsche, Johannes Harter, Magdalena Feldhahn, Yannick Bantel, Janina Johänning, Jiri Ködding, Dirk Hadaschik, Martin Schulze, Florian Battke, Olga Maksimovic, Veit Scheble, Alexandra M Miller, Michael Castro, Deborah T Blumenthal, Martin Glas, David Reardon, Saskia Biskup","doi":"10.1136/jitc-2024-011070","DOIUrl":"10.1136/jitc-2024-011070","url":null,"abstract":"<p><p>Isocitrate dehydrogenase (IDH) mutant glioma is a malignant primary brain tumor diagnosed in adults. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors. The first targeted IDH-inhibitor was approved by the US Food and Drug Administration in August 2024 for grade 2 gliomas, in light of results of a phase III trial which showed significant advantages in progression-free survival. However, biologic therapy is not curative, and subsequent treatment options offer only limited clinical benefit and often result in long-term toxicities. In addition, targeted treatment options for grade 3 and grade 4 IDH-mutant gliomas are still missing. In this study, we present n=52 patients with glioma (grade 2, 3 and 4) with confirmed IDH1 mutation (mutIDH1) in the newly diagnosed and recurrent setting who, in addition to standard-of-care, received a personalized neoantigen-targeting peptide vaccine. Each tumor was initially analyzed for somatic mutations by whole exome sequencing, and a peptide vaccine containing potential neoepitopes was designed, manufactured and vaccinated. Each vaccine consisted of peptides derived from numerous somatic mutations, including at least one peptide targeting the mutIDH1.Vaccine immunogenicity was determined by intracellular cytokine staining and simultaneous measurement of four T-cell activation markers (Interferon-γ, Tumor Necrosis Factor, Interleukin-2, CD154) after 12-day in vitro expansion of pre and post vaccination peripheral blood mononuclear cells. Extracellular CD154 staining was used to sort mutIDH1-specific CD4+T cells.Immunomonitoring revealed that the vaccines were immunogenic and induced mainly CD4 but also CD8 T cell responses. Vaccine-induced immune responses were robust and polyfunctional. Immunogenicity against mutIDH1 was high (89%). We implemented an assay which allowed us to isolate functional antigen-specific CD4+T cells in an HLA-independent manner. Subsequent T cell receptor (TCR) repertoire sequencing revealed that CD4+T cells reacting on mutIDH1 stimulation were polyclonal. Strikingly, we detected two mutIDH1-specific TCRβ candidate sequences in three different patients. These three patients had the same human leukocyte antigen (HLA) DQA-DQB alleles. The obtained TCRβ sequences could be tracked in autologous ex-vivo single-cell transcriptomic data. Our results provide a rationale for pursuing vaccination and T cell transfer strategies targeting IDH1. Furthermore, our findings indicate that personalized neoantigen-targeting vaccines might be considered for the treatment of IDH1-mutant gliomas.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247943","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}
Yingqi Hua, Chongren Wang, Fan Li, Yanjie Han, Dongqing Zuo, Yu Lv, Mengxiong Sun, Peng Yuan, Ruirong Yuan, Fan Zhang, Liang Ma, Yan Wang, Hui Wu, Guoqing Zhou, Qiang Lin, Shuhang Wang, Ning Li, Yinying Lu
{"title":"Phase 1, open-label, multicenter, dose escalation safety and tolerability study of oncolytic virus OVV-01 in advanced solid tumors.","authors":"Yingqi Hua, Chongren Wang, Fan Li, Yanjie Han, Dongqing Zuo, Yu Lv, Mengxiong Sun, Peng Yuan, Ruirong Yuan, Fan Zhang, Liang Ma, Yan Wang, Hui Wu, Guoqing Zhou, Qiang Lin, Shuhang Wang, Ning Li, Yinying Lu","doi":"10.1136/jitc-2025-011517","DOIUrl":"10.1136/jitc-2025-011517","url":null,"abstract":"<p><strong>Background: </strong>OVV-01 is a genetically engineered vesicular stomatitis virus oncolytic virus designed to selectively amplify in tumor cells and express tumor-associated antigen NY-ESO-1. This study was designed to evaluate the safety, tolerability, and efficacy of OVV-01 in patients with advanced solid tumors.</p><p><strong>Methods: </strong>This is a phase 1, first-in-human, open-label, multicenter study of OVV-01 in patients with advanced solid tumors. OVV-01 was intratumorally injected biweekly (every two weeks, Q2W), 3 weeks after the first dose for a total of six doses. Dose escalation follows a 3+3 design at four doses of 6×10<sup>7</sup> Plaue-Forming Unit (PFU), 6×10<sup>8</sup> PFU, 6×10<sup>9</sup> PFU, and 1.2×10<sup>11</sup> PFU. The primary endpoints were safety and tolerability. The second endpoints included overall response rate (ORR) and disease control rate (DCR) of OVV-01, by investigators per Response Evaluation Criteria in Solid Tumors V.1.1.</p><p><strong>Results: </strong>18 patients were enrolled into four dose groups, among whom 6 were soft tissue sarcoma (STS). No dose-limiting toxicities and treatment-related severe adverse events were observed. 11 patients were evaluated for efficacy, and the ORR was 27.3%, and the DCR was 63.6%. Among the four evaluable patients with advanced STS, the ORR was 75%. Two patients with STS achieved CR at doses above 6.0×10<sup>9</sup> PFU.</p><p><strong>Conclusions: </strong>The intratumor injection of OVV-01 was safe and well-tolerated in patients with advanced solid tumors. A significant response was observed in patients with STS.</p><p><strong>Trial registration number: </strong>NCT04787003.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247945","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}
Liwei Zhao, Peng Liu, Allan Sauvat, Killian Carnet Le Provost, Jiani Liu, Andrea Checcoli, Jonathan Pol, Oliver Kepp, Guido Kroemer, Lucillia Bezu
{"title":"Dexmedetomidine induces immunogenic cancer cell death and sensitizes tumors to PD-1 blockade.","authors":"Liwei Zhao, Peng Liu, Allan Sauvat, Killian Carnet Le Provost, Jiani Liu, Andrea Checcoli, Jonathan Pol, Oliver Kepp, Guido Kroemer, Lucillia Bezu","doi":"10.1136/jitc-2024-010714","DOIUrl":"10.1136/jitc-2024-010714","url":null,"abstract":"<p><strong>Background: </strong>Local anesthetics promote anticancer immune responses. A machine learning-based algorithm trained with information on the biological effects and molecular descriptors of analgesics, anesthetics, hypnotics and opioids predicted antitumor effects for dexmedetomidine (DEX). DEX is a sedative acting as an alpha2-adrenoceptor (ADRA2) agonist. Based on these premises, we investigated the putative antineoplastic effects of DEX.</p><p><strong>Results: </strong>In vitro, DEX promoted premortem stresses such as autophagy and partial endoplasmic reticulum stress with the phosphorylation of eukaryotic initiation factor 2 alpha and the inhibition of the splicing of X-box binding protein 1. DEX elicited the biomarkers of immunogenic cell death, including the release of ATP and high-mobility group box 1 protein, and the cell surface exposure of calreticulin, enhancing the engulfment of malignant cells by dendritic cells. In immunocompetent mice, DEX decreased the progression of colorectal cancers, fibrosarcomas, mammary carcinomas and melanomas, as it improved overall survival. These effects were inhibited by the ADRA2 antagonist yohimbine, suggesting that DEX mediates its anticancer effects at least in part on-target. Depending on the specific tumor model, DEX also enhanced the cytotoxic T cell/regulatory T cell ratio in the tumor bed and draining lymph nodes. Programmed cell death protein 1 blockade tended to improve DEX effects. After rechallenge with antigenically identical cells, no tumor appeared, indicating the formation of immunological memory.</p><p><strong>Conclusions: </strong>These results confirm the machine learning-predicted anticancer activity of DEX. Beyond its utility as a sedative agent in oncological intensive care, DEX may improve anticancer immunosurveillance and sensitize tumors to immune checkpoint blockade.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247941","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}
Liu Zhaoyun, Hao Wang, Chun Yang, Xianghong Zhao, Liu Hui, Jia Song, Kai Ding, Rong Fu
{"title":"Enhancing antitumor immunity via ROS-ERS and pyroptosis-induced immunogenic cell death in multiple myeloma.","authors":"Liu Zhaoyun, Hao Wang, Chun Yang, Xianghong Zhao, Liu Hui, Jia Song, Kai Ding, Rong Fu","doi":"10.1136/jitc-2025-011717","DOIUrl":"10.1136/jitc-2025-011717","url":null,"abstract":"<p><strong>Background: </strong>Few studies have focused on the development of multiple myeloma (MM)-specific immunotherapies. Tumor immunogenic cell death (ICD), triggered by damage-associated molecular patterns, may enhance MM-specific antitumor activity, offering a potential treatment strategy.</p><p><strong>Methods: </strong>This study confirms that combining reactive oxygen species (ROS)-endoplasmic reticulum stress (ERS) and pyroptosis-inducers (ROS-ERS inducer 1 (REI) and Quillaja saponaria fraction 21 (QS-21), respectively) activates specific anti-MM immunity. MM cell lines were treated with REI and QS-21 alone or in combination and cytotoxicity and apoptosis were examined. ICD markers were identified, including calreticulin, ATP, heat shock protein 70, and high mobility group box 1. Additionally, changes in mitochondrial damage, endoplasmic reticulum stress, pyroptosis markers, and immune markers of dendritic cell (DC) maturation and T-cell activation were assessed both in vitro and in vivo.</p><p><strong>Results: </strong>ROS-ERS combined with pyroptosis significantly induces MM cell apoptosis and enhances ICD marker activation. The combination treatment induces severe mitochondrial damage and endoplasmic reticulum stress, further promoting pyroptosis and MM-specific T-cell activation. In vivo, the combination treatment reduces tumor growth and improves DC and T-cell activation.</p><p><strong>Conclusions: </strong>Thus, ROS-ERS inducers and pyroptosis inducers together significantly enhance the immunogenic response against MM, providing a promising strategy for MM treatment by activating powerful specific T-cell antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234152","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}
Julia Werner, Haifeng C Xu, Georgios Theodorakis, Ichiro Katahira, Mitrajit Ghosh, Michal Gorzkiewicz, Luisa de Sousa Santos, Ann Kathrin Bergmann, Max Anstötz, Anne Busch, Diran Herebian, Sascha Dietrich, Carsten Berndt, Ertan Mayatepek, Aleksandra A Pandyra, Dirk Brenner, Philipp A Lang
{"title":"Myoglobin expression improves T-cell metabolism and antitumor effector function.","authors":"Julia Werner, Haifeng C Xu, Georgios Theodorakis, Ichiro Katahira, Mitrajit Ghosh, Michal Gorzkiewicz, Luisa de Sousa Santos, Ann Kathrin Bergmann, Max Anstötz, Anne Busch, Diran Herebian, Sascha Dietrich, Carsten Berndt, Ertan Mayatepek, Aleksandra A Pandyra, Dirk Brenner, Philipp A Lang","doi":"10.1136/jitc-2025-011503","DOIUrl":"10.1136/jitc-2025-011503","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment is frequently hypoxic and characterized by a scarcity of nutritional resources including a shortage of glucose. As effector T cells have high energy demands, tumor metabolism can contribute to T-cell dysfunction and exhaustion.</p><p><strong>Methods: </strong>In this study, we determined hypoxia in spleen and tumor tissue from tumor-bearing C57BL/6J mice using reverse transcription polymerase chain reaction (RT-PCR), histology and flow cytometry. Next, CD8<sup>+</sup> T cells isolated from C57BL6J mice or P14<sup>+</sup> mice were transduced with Thy1.1 (Control) or Thy1.1-Myoglobin (Mb) packaged retrovirus. Expression of Mb was confirmed with RT-PCR and western blot. Cellular metabolism was determined by flow cytometry, transmission electron microscopy, focused ion beam scanning electron microscopy, Seahorse, metabolomics and luminescence assays. Mb expressing or control P14<sup>+</sup> or OT-I<sup>+</sup> T cells were transferred in B16F10-gp33 or MC38-ova tumor-bearing mice respectively and analyzed using flow cytometry and histology. B16F10-gp33 tumor-bearing mice were additionally treated with anti-programmed cell death protein-1 (PD-1) checkpoint inhibitor.</p><p><strong>Results: </strong>Here we demonstrate that expression of the oxygen-binding protein myoglobin in T cells can boost their mitochondrial and glycolytic metabolic functions. Metabolites and tricarboxylic acid compounds were highly increased in the presence of myoglobin (Mb), which was associated with increased ATP levels. Mb-expressing T cells exhibited low expression of hypoxia-inducible factor-1α after activation and during infiltration into the tumor microenvironment (TME). Accordingly, Mb expression increased effector T-cell function against tumor cells in vitro with concomitant reductions in superoxide levels. Following adoptive transfer into tumor-bearing mice, Mb expression facilitated increased infiltration into the TME. Although T cells expressing Mb exhibited increased expression of effector cytokines, PD-1 was still detected and targetable by anti-PD-1 monoclonal antibodies, which in combination with transfer of Mb-expressing T cells demonstrated maximal efficacy in delaying tumor growth.</p><p><strong>Conclusion: </strong>Taken together, we show that expression of Mb in T cells can increase their metabolism, infiltration into the tumor tissue, and effector function against cancer cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215893","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}
Dong-Wen Chen, Yi-Kan Cheng, Pei-Si Li, Xiao-Jian Wu, Xin-Xin Huang, Jia-Hui Long, Zhizhong Xiong, Chong Chen, Shu-Biao Ye, Ping Lan
{"title":"Tumor-intrinsic TTLL12 drives resistance to cancer immunotherapy via modulating myeloid-derived suppressor cells.","authors":"Dong-Wen Chen, Yi-Kan Cheng, Pei-Si Li, Xiao-Jian Wu, Xin-Xin Huang, Jia-Hui Long, Zhizhong Xiong, Chong Chen, Shu-Biao Ye, Ping Lan","doi":"10.1136/jitc-2024-010873","DOIUrl":"10.1136/jitc-2024-010873","url":null,"abstract":"<p><strong>Background: </strong>The majority of patients treated with immunotherapy as a standalone therapy experience little to no benefits. Tubulin tyrosine ligase 12 (TTLL12), as a member of the tubulin tyrosine ligase protein family, is associated with the prognosis of patients with cancer and implicated in regulating innate immunity. However, the role of TTLL12 in modulating antitumor immunity remains unclear.</p><p><strong>Methods: </strong>We analyzed the expression of TTLL12 in several cancer types and evaluated the putative correlation between TTLL12 expression and the immune infiltration in our own proteomic profile of human colorectal cancer. The gain-of-function or loss-of-function approaches were then implemented in vitro and in vivo, followed by flow cytometry to quantify immune cell population frequency. In vitro assays were used to confirm the influence of TTLL12 on the migration and proliferation of the immune subset. Mass spectrometry and chromatin-immunoprecipitation were used to further explore how TTLL12 influenced the immune subset. Finally, whether TTLL12 could enhance the antitumor efficacy of anti-programmed cell death protein 1 (PD-1) therapy was assessed in an immunocompetent mouse model.</p><p><strong>Results: </strong>We demonstrated that TTLL12 was upregulated in several cancer types and was linked with poor prognosis in patients with colorectal cancer. TTLL12 was found to be negatively correlated with the immune effector signature on the protein level in our proteomic datasets. TTLL12 ectopic expression in tumor cells did not influence cell proliferation but promoted tumor progression in syngeneic mouse models by modulating myeloid-derived suppressor cells (MDSCs), resulting in a suppressive immune response. TTLL12 was further proved to enrich MDSCs by promoting MDSC migration and proliferation in vitro. Mechanistically, tumor-derived TTLL12 induced the secretion of chemokine CCL9 via promoting its transcription, probably through binding to the promoter region of CCL9. Downregulating TTLL12 could significantly improve the efficacy of anti-PD-1 therapy in an immunocompetent murine model.</p><p><strong>Conclusion: </strong>We identify TTLL12 as a key determinant of suppressive immune response, highlighting a previously unknown therapeutic target to increase the efficacy of antitumor immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215894","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}
Michael Volkmar, Dana Hoser, Claudia Lauenstein, Janina Rebmann, Agnes Hotz-Wagenblatt, Jan Rieger, Isabel Poschke, Jonas P Becker, Angelika B Riemer, Martin Sprick, Andreas Trumpp, Oliver Strobel, Thomas Blankenstein, Gerald Willimsky, Rienk Offringa
{"title":"Enhanced mutanome analysis towards the induction of neoepitope-reactive T-cell responses for personalized immunotherapy of pancreatic cancer.","authors":"Michael Volkmar, Dana Hoser, Claudia Lauenstein, Janina Rebmann, Agnes Hotz-Wagenblatt, Jan Rieger, Isabel Poschke, Jonas P Becker, Angelika B Riemer, Martin Sprick, Andreas Trumpp, Oliver Strobel, Thomas Blankenstein, Gerald Willimsky, Rienk Offringa","doi":"10.1136/jitc-2025-011802","DOIUrl":"10.1136/jitc-2025-011802","url":null,"abstract":"<p><strong>Background: </strong>Personalized immunotherapy of pancreatic ductal adenocarcinoma (PDAC) through T-cell mediated targeting of tumor-specific, mutanome-encoded neoepitopes may offer new opportunities to combat this disease, in particular by countering recurrence after primary tumor resection. However, the sensitive and accurate calling of somatic mutations in PDAC tissue samples is compromised by the low tumor cell content. Moreover, the repertoire of immunogenic neoepitopes in PDAC is limited due to the low mutational load of the majority of these tumors.</p><p><strong>Methods: </strong>We developed a workflow involving the combined analysis of next-generation DNA and RNA sequencing data from matched pairs of primary tumor samples and patient-derived xenograft models towards the enhanced detection of driver mutations as well as single nucleotide variants encoding potentially immunogenic T-cell neoepitopes. Subsequently, we immunized HLA/human T-cell receptor (TCR) locus-transgenic mice with synthetic peptides representing candidate neoepitopes, and molecularly cloned the genes encoding TCRs targeting these epitopes.</p><p><strong>Result: </strong>Application of our pipeline resulted in the identification of greater numbers of non-synonymous mutations encoding candidate neoepitopes with increased confidence. Furthermore, we provide proof of concept for the successful isolation of HLA-restricted TCRs from humanized mice immunized with different neoepitopes, several of which would not have been selected based on mutanome analysis of PDAC tissue samples alone. These TCRs mediate specific T-cell reactivity against the tumor cells in which the corresponding mutations were identified.</p><p><strong>Conclusion: </strong>Enhanced mutanome analysis and candidate neoepitope selection increase the likelihood of identifying therapeutically relevant neoepitopes, and thereby support the optimization of personalized immunotherapy for PDAC and other poorly immunogenic cancers.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215892","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}