Journal for Immunotherapy of Cancer最新文献

{"title":"Chemotherapy-induced cellular senescence promotes stemness of aggressive B-cell non-Hodgkin's lymphoma via CCR7/ARHGAP18/IKBα signaling activation.","authors":"Jiyu Wang, Qianshan Tao, Keke Huang, Yangyang Wang, Linhui Hu, Anwen Ren, Huiping Wang, Yang Wan, Jinlan Li, Liuying Yi, Yanjie Ruan, Zhixiang Wanyan, Fan Wu, Zhimin Zhai, Chaohong Liu","doi":"10.1136/jitc-2024-009356","DOIUrl":"10.1136/jitc-2024-009356","url":null,"abstract":"<p><strong>Background: </strong>Resistance to existing therapies is a major cause of treatment failure in patients with refractory and relapsed B-cell non-Hodgkin's lymphoma (r/r B-NHL). Therapy-induced senescence (TIS) is one of the most important mechanisms of drug resistance.</p><p><strong>Methods: </strong>This study used single-cell RNA sequencing to analyze doxorubicin-induced senescent B-NHL cells. C-C chemokine receptor 7 (CCR7) expression in patients with aggressive B-NHL was assessed using immunohistochemistry and flow cytometry. Lentiviral transfection was used to target CCR7 expression in Raji and SU-DHL-2 cells. Protein localization was visualized through immunofluorescence, while western blotting and co-immunoprecipitation were used to analyze protein expression and interactions. Cell proliferation was measured with the Cell Counting Kit-8 assay, and senescent cells were detected using senescence-associated β-galactosidase staining. The stemness of cells was evaluated through colony and sphere formation assays. Transwell assays assessed cell migration and invasion. Finally, inhibitors GS143 and Y27632 were used to examine the effect of IKBα and ARHGAP/RhoA inhibition on B-NHL-TIS.</p><p><strong>Results: </strong>Here we identified a distinct group of TIS, composed of memory B-cell population characterized by strong positive expression of CCR7, which was significantly elevated in TIS population compared with normal proliferating and autonomously senescent lymphoma cell populations. Additionally, CCR7 expression was significantly upregulated in patients with r/r B-NHL, and was an independent prognostic factor in B-NHL, with high CCR7 expression being strongly associated with poor prognosis. In vitro results indicated that CCL21 induced migration and invasion of B-NHL cells via CCR7, while blocking CCR7 reduced doxorubicin-induced migration and invasion of these cells. Furthermore, B-NHL-TIS regulated by CCR7 and exhibited enhanced phenotypic and functional stemness features, including the upregulation of stemness markers, increased colony-forming, invasive and migratory capabilities. Mechanistically, blocking CCR7 reversed the stemness characteristics of senescent B-NHL cells by inhibiting the activation of ARHGAP18/IKBα signaling.</p><p><strong>Conclusions: </strong>Together, TIS promotes the stemness of B-NHL cells via CCR7/ARHGAP18/IKBα signaling activation and targeting CCR7/ARHGAP18 might overcome the chemoresistance of senescent B-NHL cells by inhibiting stemness acquisition and maintenance.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949194","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":"Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment.","authors":"Jacob Gadwa, Justin Yu, Miles Piper, Michael W Knitz, Laurel B Darragh, Nicholas Olimpo, Sophia Corbo, Jessica I Beynor, Brooke Neupert, Alexander T Nguyen, Chloe Hodgson, Diemmy Nguyen, Khalid Nm Abdelazeem, Anthony Saviola, Laurene Pousse, Ali Bransi, Mudita Pincha, Christian Klein, Maria Amann, Sana D Karam","doi":"10.1136/jitc-2024-010405","DOIUrl":"10.1136/jitc-2024-010405","url":null,"abstract":"<p><strong>Background: </strong>Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.</p><p><strong>Methods: </strong>Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.</p><p><strong>Results: </strong>By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression.</p><p><strong>Conclusions: </strong>This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949201","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":"Safety and efficacy of the therapeutic DNA-based vaccine VB10.16 in combination with atezolizumab in persistent, recurrent or metastatic HPV16-positive cervical cancer: a multicenter, single-arm phase 2a study.","authors":"Peter Hillemanns, Michal Zikan, Frédéric Forget, Hannelore G Denys, Jean-Francois Baurain, Lukas Rob, Linn Woelber, Pawel Blecharz, Mariusz Bidzinski, Josef Chovanec, Frederik Marmé, Theresa Link, Christian Dannecker, Anders Rosholm, Kaja C G Berg, Roberto S Oliveri, Kristina Lindemann","doi":"10.1136/jitc-2024-010827","DOIUrl":"10.1136/jitc-2024-010827","url":null,"abstract":"<p><strong>Background: </strong>Second-line treatment options for persistent, recurrent or metastatic (r/m) cervical cancer are limited. We investigated the safety, efficacy, and immunogenicity of the therapeutic DNA-based vaccine VB10.16 combined with the immune checkpoint inhibitor atezolizumab in patients with human papillomavirus (HPV)16-positive r/m cervical cancer.</p><p><strong>Patients and methods: </strong>This multicenter, single-arm, phase 2a study (NCT04405349, registered 26 May 2020) enrolled adult patients with persistent, r/m HPV16-positive cervical cancer. Patients received 3 mg VB10.16 (every 3 weeks (Q3W) for 12 weeks, hereafter every 6 weeks) combined with 1,200 mg atezolizumab (Q3W) for 48 weeks in total with a 12-month follow-up. The primary endpoints were incidence and severity of adverse events (AEs) and objective response rate (ORR; Response Evaluation Criteria in Solid Tumor V.1.1). ORR was assessed in the efficacy population, being all response-evaluable patients who received any administration of VB10.16 and atezolizumab and had at least one post-baseline imaging assessment.</p><p><strong>Results: </strong>Between June 16, 2020, and January 25, 2022, 52 patients received at least one administration of study treatment. Of these, 47 patients had a minimum of one post-baseline tumor assessment. The median follow-up time for survival was 11.7 months. AEs related to VB10.16 were non-serious and mainly mild injection site reactions (9 of 52 patients). There were no signs of new toxicities other than what was already described with atezolizumab. ORR was 19.1% (95% CI 9.1% to 33.3%). Median duration of response was not reached (n.r.) (95% CI 2.2 to n.r.), median progression-free survival was 4.1 months (95% CI 2.1 to 6.2), and median overall survival was 21.3 months (95% CI 8.5 to n.r.). In programmed death-ligand 1 (PD-L1)-positive patients (n=24), ORR was 29.2% (95% CI 12.6 to 51.1). HPV16-specific T-cell responses were analyzed in 36 of 47 patients with an increase observed in 22/36 (61%).</p><p><strong>Conclusions: </strong>The therapeutic DNA-based vaccine VB10.16 combined with atezolizumab was safe and well tolerated showing a promising clinically meaningful efficacy with durable responses in patients with persistent, r/m HPV16-positive cervical cancer, especially if PD-L1-positive.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949215","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":"Durvalumab and tremelimumab in combination with metronomic oral vinorelbine for recurrent advanced cervical cancer: an open-label phase I/II study.","authors":"Jean-Sébastien Frenel, Laurent Mathiot, Claire Cropet, Edith Borcoman, Alice Hervieu, Elodie Coquan, Thibault De La Motte Rouge, Esma Saada-Bouzid, Renaud Sabatier, Pernelle Lavaud, Marta Jimenez, François Legrand, Olivia Le Saux, Emmanuelle Charafe, Anthony Gonçalves","doi":"10.1136/jitc-2024-010708","DOIUrl":"10.1136/jitc-2024-010708","url":null,"abstract":"<p><strong>Background: </strong>The MOVIE phase I/II trial (NCT03518606) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort.</p><p><strong>Methods: </strong>Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression. The primary efficacy endpoint was the clinical benefit rate (CBR) based on the Response Evaluation Criteria in Solid Tumors V.1.1, which was analyzed using a Bayesian approach RESULTS: A total of 31 patients were enrolled and treated in the cervical cancer cohort. The median number of previous lines of chemotherapy for advanced disease was 2 (0-6), with all (100%) and 12 (38.7%) patients pretreated with cisplatin and bevacizumab, respectively. At the data cut-off, the median follow-up duration was 12.8 (Q1-Q3, 6.1-34.6) months. The CBR was 53.1% (95% CI, 36.0% to 69.8%), using a non-informative prior distribution (beta(1, 1)). The overall response rate was 41.9%, five patients achieved a complete response (16.1%), and eight patients (25.8%) had a partial response irrespective of histological subtype or programmed death-ligand 1 (PD-L1) expression. Of the 31 patients, 28 (90.3%) experienced treatment-related adverse events (TRAEs), 13 (41.9%) reported grade ≥3 immune-related adverse events (AEs), and 13 (41.9%) reported grade ≥3 chemotherapy-related AEs. The definitive discontinuation rate due to TRAEs was 16.1%.</p><p><strong>Conclusions: </strong>Dual checkpoint blockade of PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 combined with metronomic oral vinorelbine demonstrated meaningful and durable clinical activity in patients with previously treated advanced cervical cancer. Toxicity was significant but manageable.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949205","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":"Intratumoral and peritumoral radiomics of MRI predicts pathologic complete response to neoadjuvant chemoimmunotherapy in patients with head and neck squamous cell carcinoma.","authors":"Jie Sun, Xuewei Wu, Ruhang Ma, Shuixing Zhang, Bin Zhang","doi":"10.1136/jitc-2024-011189","DOIUrl":"https://doi.org/10.1136/jitc-2024-011189","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023459","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":"New developments in immunotherapy for SCLC.","authors":"Tsering Dolkar, Christopher Gates, Zhonglin Hao, Reinhold Munker","doi":"10.1136/jitc-2024-009667","DOIUrl":"10.1136/jitc-2024-009667","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive form of neuroendocrine neoplasm known for its striking initial response to treatment, followed by fast relapse and refractoriness in response to additional lines of therapy. New advances in immunotherapy are paving the way for more effective treatment strategies and have promising results with early clinical trial data. While SCLC rarely harbors actionable mutations, the receptor DLL3 is extensively present in SCLC, making it a potential target for immunotherapy. Three emerging therapeutic options include bispecific T cell engagers targeting DLL3, chimeric antigen receptor T cells (CAR-T cells), and antibody-drug conjugates. Several phase II and phase III clinical trials for bispecific T cell engagers show promise. Additionally, the first CAR-T cell trials in humans for SCLC are currently underway.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949207","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":"Novel and potent MICA/B antibody is therapeutically effective in <i>KRAS LKB1</i> mutant lung cancer models.","authors":"Ryan R Kowash, Manoj Sabnani, Laura T Gray, Qing Deng, Nusrat U A Saleh, Luc Girard, Yujiro Naito, Kentaro Masahiro, John D Minna, David E Gerber, Shohei Koyama, Zhiqian Lucy Liu, Hemanta Baruah, Esra A Akbay","doi":"10.1136/jitc-2024-009867","DOIUrl":"10.1136/jitc-2024-009867","url":null,"abstract":"<p><strong>Background: </strong>Concurrent <i>KRAS LKB1</i> (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through activation of natural killer (NK) cells.</p><p><strong>Methods: </strong>Expression of NK cell activating ligands in NSCLC cell line and patient data were analyzed. Cell surface expression of MICA/B in NSCLC cell lines was determined through flow cytometry while ligand shedding in both patient blood and cell lines was determined through ELISA. We engineered an antibody-dependent cellular cytotoxicity (ADCC) enhanced MICA/B monoclonal antibody, AHA-1031, which prevents ligand shedding without interfering with binding to natural killer group 2D while targeting cancer cells via superior ADCC. We performed in vitro assays using ELISA and flow cytometry-based assays to confirm that our antibody potently binds to and stabilizes MICA/B expression across lung cancer and other solid tumor cell lines. Additionally, we used two KL mutant NSCLC cell lines and a KL mutant patient-derived xenograft (PDX) model to demonstrate in vivo antitumor efficacy and flow cytometry analysis for immune cell activation profiling.</p><p><strong>Results: </strong>NSCLC cell lines exhibit high MICA/B expression and secrete soluble MICA/B in vitro. Soluble MICA/B is also detected in patient blood samples. AHA-1031 binds to the α3 domain of MICA/B, preventing shedding and targeting tumor cells to ADCC. AHA-1031 exhibits high affinity and specificity to MICA/B, preventing MICA/B shedding in tumor lines and inducing ADCC in vitro. Our antibody also effectively binds and stabilizes MICA/B expression in additional tumor types and demonstrates broad specificity. We show that in two KL mutant NSCLC xenograft models and a KL mutant PDX model, treatment with AHA-1031 monotherapy significantly inhibits tumor growth compared with vehicle-treated animals with no observable toxicity. Tumor tissues from treated mice exhibit significantly increased immune cell infiltrates and activated NK cell populations.</p><p><strong>Conclusions: </strong>Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949211","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-PD-1 amplifies costimulation in melanoma-infiltrating T_h1-like Foxp3⁺ regulatory T cells to alleviate local immunosuppression.","authors":"Mikhaël Attias, Fernando Alvarez, Tho-Alfakar Al-Aubodah, Roman Istomine, Paige McCallum, Fan Huang, Abrahim Sleiman, Tamiko Nishimura, Sonia V Del Rincón, Yasser Riazalhosseini, Ciriaco A Piccirillo","doi":"10.1136/jitc-2024-009435","DOIUrl":"10.1136/jitc-2024-009435","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1) are the first line of treatment for many solid tumors including melanoma. PD-1 blockade enhances the effector functions of melanoma-infiltrating CD8⁺ T cells, leading to durable tumor remissions. However, 55% of patients with melanoma do not respond to treatment. As Foxp3⁺ regulatory T (T_reg) cells play an important role in tumor-induced immunosuppression and express PD-1, we hypothesized that anti-PD-1 also increases the functions of melanoma-infiltrating T_reg cells, which could be detrimental to treatment efficacy.</p><p><strong>Methods: </strong>The cellular and functional dynamics of T_reg cells were evaluated in C57Bl/6 Foxp3-reporter mice bearing highly immunogenic and PD-1 blockade-sensitive Yale University Mouse Melanoma Exposed to Radiation 1.7 (YUMMER1.7) tumors. T_reg cell responses in tumors and lymphoid compartments were examined throughout tumor growth or therapy and were assessed ex vivo by multiparametric flow cytometry analysis, with in vitro suppression assays using tumor-infiltrating lymphocytes isolated by fluorescence-activated cell sorting (FACS) and <i>in situ</i> through spatial proteomic and transcriptomic profiling.</p><p><strong>Results: </strong>In this highly immunogenic melanoma model, anti-PD-1 monotherapy yielded high responders (HRs) and low responders (LRs). We show that the potent CD8⁺ T cell responses characteristic of HR tumors paradoxically coincide with the expansion of highly-activated, Helios-expressing T_reg cells. In both HRs and LRs, T_reg cells co-localize with CD8⁺ T cells in immunogenic regions of the tumor and display potent suppressive capacity in vitro. Further characterization revealed that melanoma-infiltrating T_reg cells progressively acquire T-bet and interferon gamma expression, exclusively in HRs, and induction of this T helper cell 1 (T_h1)-like phenotype in vitro led to CD8⁺ T cell evasion from T_reg cell-mediated suppression. Using spatial proteomic and transcriptomic profiling, we demonstrate that T_reg cells display an increased activity of PI3K/Akt signaling in regions of HR tumors with an elevated CD8:T_reg cell ratio.</p><p><strong>Conclusions: </strong>PD-1 blockade promotes the expansion of a subset of highly-activated T_reg cells coexpressing PD-1 and Helios. While these cells are potently suppressive outside tumor environments, costimulatory and inflammatory signals present in the tumor microenvironment lead to their local acquisition of T_h1-like characteristics and loss of suppression of effector T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005620","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":"GP73 reinforces cytotoxic T-cell function by regulating HIF-1α and increasing antitumor efficacy.","authors":"Jialong Liu, Chao Feng, Ruzhou Zhao, Hongbin Song, Linfei Huang, Nan Jiang, Xiaopan Yang, Lanlan Liu, Cuijuan Duan, Luming Wan, Qi Gao, Lijuan Sun, Xufeng Hou, Muyi Liu, Yanhong Zhang, Xuemiao Zhang, Dandan Zhang, Yufei Wang, Yong Li, Xueping Ma, Hui Zhong, Min Min, Congwen Wei, Yuan Cao, Xiaoli Yang","doi":"10.1136/jitc-2024-009265","DOIUrl":"10.1136/jitc-2024-009265","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy that targets immune checkpoints has achieved revolutionary success, but its application in solid tumors remains limited, highlighting the need for reliable enhancement of the efficacy of immunotherapy. Golgi protein 73 (GP73), a Golgi membrane protein, has been implicated in various cellular processes, including immune regulation. Recent studies suggested that GP73 may play a role in modulating the immune response in patients with cancer. In this study, we investigated the mechanism by which GP73 regulates T-cell-mediated antitumor immunity within the tumor microenvironment.</p><p><strong>Methods: </strong>We used T-cell specific GP73 knockout mice to establish MC38 and B16 tumor models to investigate the impact of GP73-deficient T cells on tumor growth. Single-cell sequencing was subsequently employed to classify tumor-infiltrating immune cells and assess changes in cytokines and metabolic genes. Through RNA sequencing, real-time quantitative PCR, western blotting, flow cytometry, seahorse analysis, glucose uptake, and L-lactic acid secretion assays, we explored how GP73 regulates hypoxia-inducible factor 1α (HIF-1α) to influence T-cell antitumor functionality. Furthermore, we established adoptive transfer experiments to study the ability of GP73-overexpressing T cells to combat tumors. Blood samples of patient with clinical tumor were collected to assess the relationship between immunotherapy efficacy and T-cell GP73 levels.</p><p><strong>Results: </strong>In this study, the absence of GP73 in mouse T cells promoted tumor growth and metastasis, accompanied by a decrease in the proportion of cytotoxic CD8+T cell subsets infiltrating the tumor and an increase in exhausted CD8+ T-cell subsets. Further analysis revealed that the effector function of CD8+T cells in tumors relies on glycolysis regulated by HIF-1α rather than immune checkpoints. GP73-deficient T cells exhibit severely impaired glycolysis in hypoxic environments, whereas ectopic GP73 expression restores HIF-1α levels. In adoptive immunotherapy, overexpression of GP73 in T cells inhibits tumor growth. In cytotoxicity assays, knockdown of GP73 affected the ability of CD8+T cells to kill target cells. Clinically, tumor immunotherapy partial response patients present significantly elevated levels of GP73 expression in T cells.</p><p><strong>Conclusions: </strong>These findings reveal the role of GP73 in regulating T-cell glycolysis and may lead to new therapeutic strategies for the prognosis and treatment of clinical tumor immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005670","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":"Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression.","authors":"Kaifeng Jin, Yawei Ding, Jingtong Xu, Zhaopei Liu, Han Zeng, Xiaohe Su, Lingkai Zhang, Jiaxing Sun, Yuzhen Wu, Hailong Liu, Yuan Chang, Yu Zhu, Zewei Wang, Le Xu, Weijuan Zhang, Jiejie Xu","doi":"10.1136/jitc-2024-010964","DOIUrl":"10.1136/jitc-2024-010964","url":null,"abstract":"<p><strong>Background: </strong>The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of <i>TP53</i> pathway, one of the three most crucial oncogenic pathways in urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of <i>MDM2</i> amplification in UC remain unclear.</p><p><strong>Methods: </strong>This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort). We assessed the correlation between <i>MDM2</i> status and clinical outcomes, therapeutic efficacy, and immunological characteristics by immunohistochemical analysis and targeted sequencing. Additionally, 2264 UC samples from five independent external cohorts, with genomic, transcriptomic, and clinical data, were used for validation.</p><p><strong>Results: </strong><i>MDM2</i> amplification (<i>MDM2</i> ^Amp) or protein overexpression (MDM2^OE) was associated with inferior overall survival (ZSHS cohort, Log-rank p<0.001; FUSCC cohort, Log-rank p=0.030) and reduced response to platinum-based chemotherapy (ZSHS cohort, Log-rank p<0.001) as well as anti-PD-1/PD-L1 immunotherapy (FUSCC cohort, Log-rank p=0.016) in patients with UC, irrespective of <i>TP53</i>/p53 status. <i>MDM2</i> amplification or overexpression was further linked to high-grade UC tumors with dedifferentiated morphology. In addition, UC with <i>MDM2</i> amplification or overexpression was associated with an immuno-evasive contexture characterized by lower proportion of tertiary lymphoid structure infiltration, lower abundance of CD8⁺ T cells, IFN-γ⁺ cells, GZMB⁺ cells, and decreased expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).</p><p><strong>Conclusions: </strong><i>MDM2</i> amplification or overexpression defines a lethal subset of patients with UC with inferior prognosis and resistance to both platinum-based chemotherapy and immunotherapy irrespective of <i>TP53</i>/p53 status. These tumors are characterized by dedifferentiated morphology and an immunosuppressive microenvironment. Accurate assessment of <i>MDM2</i> status can improve risk stratification and enable personalized genomics-guided treatment for patients with UC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005693","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}