Journal for Immunotherapy of Cancer最新文献

{"title":"Hyperglycemia induces an immunosuppressive microenvironment in colorectal cancer liver metastases by recruiting peripheral blood monocytes through the CCL3-CCR1 axis.","authors":"Han Peng, Yuwei Pan, Yixin Sun, Xuesong Wang, Xue Fan, Yajuan Wang, Lintao Zhao, Xi Li, Yan Dong, Jianfang Chen, Jie Zhou, Yun Du, Qing Yu, Yongtao Yang, Yue Zhang, Jianjun Li, Houjie Liang, Shuo Huang","doi":"10.1136/jitc-2024-011310","DOIUrl":"10.1136/jitc-2024-011310","url":null,"abstract":"<p><strong>Background: </strong>The treatment of colorectal cancer liver metastasis (CRLM), a leading cause of mortality in patients with colorectal cancer, is complicated by type 2 diabetes (T2D). This study aimed to investigate the CRLM immune microenvironment in the context of T2D and identify potential therapeutic targets.</p><p><strong>Methods: </strong>A hyperglycemic CRLM mouse model was established. Seven single-cell RNA sequencing datasets were analyzed, including three peripheral blood mononuclear cells (PBMCs) datasets (from healthy donors and T2D patients) and four datasets with 20 CRLM samples and matching PBMCs datasets, to explore the immune characteristics and remodeling of the tumor microenvironment in CRLM with concurrent T2D.</p><p><strong>Results: </strong>CD8⁺T cells exhibited dysfunction and exhaustion in liver metastasis from patients with CRLM and T2D; the proportions of various CD4⁺T cell subpopulations were also altered, and the number of myeloid cells and their function was increased. Myeloid cells in CRLM from patients with T2D exhibited high expression levels of CCL3, which recruited peripheral blood monocytes expressing high levels of CCR1, leading to an accumulation of myeloid cells and an immunosuppressive tumor microenvironment. Recruited cells exhibited enhanced T cell communication abilities, indicating an augmented immunosuppressive capacity. In addition, CCR1 expression in peripheral blood monocytes from patients with CRLM was closely correlated with the immunosuppressive tumor microenvironment, suggesting that CCR1 expression levels may predict immune cell phenotype and prognosis in patients with CRLM and T2D.</p><p><strong>Conclusions: </strong>Our study revealed complex changes in the tumor microenvironment of patients with CRLM and T2D. In particular, a novel mechanism was identified by which hyperglycemia regulates immunosuppression: the CCL3-CCR1 signaling axis. This finding offers a novel potential therapeutic target for patients with CRLM and T2D and provides an important theoretical basis for the future prediction of the prognosis of these patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475332","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 fusion superkine, <i>IL-24S/IL-15</i>, enhances immunotherapy of brain cancer.","authors":"Amit Kumar, Praveen Bhoopathi, Padmanabhan Mannangatti, Santanu Maji, Anjan K Pradhan, Esha Madan, Alexander L Klibanov, Rajan Gogna, David D Limbrick, Luni Emdad, Swadesh K Das, Paul B Fisher","doi":"10.1136/jitc-2024-011198","DOIUrl":"10.1136/jitc-2024-011198","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is a rapidly growing, aggressive brain tumor with very poor prognosis without currently effective therapies. The immunosuppressive nature of the tumor microenvironment (TME) in GBM hinders the development of effective tumor-eradicating immunotherapies. This hostile TME can be modulated by administering immune-activating cytokines in combination with agents inducing tumor cell death. To achieve these objectives, we sought to harness the cancer-selective cell death-inducing properties of an enhanced \"Superkine\" version of melanoma differentiation associated gene-7/interleukin-24, <i>IL-24S</i>, and the immune-activating properties of <i>IL-15</i> to modulate the TME of GBM to maximize therapeutic outcomes.</p><p><strong>Methods: </strong>A fusion \"Superkine\" (<i>FSK</i>) comprised of <i>IL-24S</i> linked to <i>IL-15</i> was generated, and antitumor effects were evaluated when transduced by a type 5 adenovirus (Ad.5) in a GBM immunocompetent mouse tumor model. To target the delivery of Ad.5 <i>FSK</i> systemically, we employed an innovative approach of focused ultrasound (FUS) paired with microbubbles (MBs), FUS-DMB (FUS plus double MB), to safely transport the <i>FSK</i> engineered Ad.5 construct into mouse brain to overcome limitations of systemic viral delivery and selectivity of the blood-brain barrier.</p><p><strong>Results: </strong>The <i>FSK</i> stimulated higher tumor regression and enhanced survival in vivo than the individual \"Superkine\" or cytokine in GBM cancer models. Apoptosis of GBM cells was induced, as well as increased tumor infiltration of T cells, dendritic cells, macrophages and natural killer (NK) cells. The antitumor-inducing activity of FSK is a consequence of induction of cancer-specific growth suppression and induction of apoptosis (IL-24S) as well as diverse effects on immune cells (IL-15 and IL-24S). Antibody neutralization indicates that a primary immune mediator of anticancer activity of FSK is through recruitment and activation of NK cells. Global cytokine analyses indicated no changes in inflammatory cytokines during therapy, suggesting that this strategy will be safe.</p><p><strong>Conclusion: </strong>In summary, treatment with an <i>FSK</i>, consisting of a fusion of <i>IL-24S</i> to <i>IL-15</i>, promotes GBM cell killing and remodeling of the TME by recruiting and activating immune cells supporting the feasibility of developing safe and effective cancer immunotherapeutic fusion proteins and selective delivery in the brain for the therapy of GBM.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475342","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":"STS2 deficiency revives CD8⁺T cells from exhaustion and augments checkpoint blockade efficacy in cancer immunotherapy.","authors":"Fangzhou Sun, Fei Ma, Ting Wang, Yantong Zhou, Dongkui Xu, Hongnan Mo, Chunxiao Li, Jianbin Guo, Zhenguo Zhao, Xiaoqi Yang, Ning Zhong, Ying Zhang, Haili Qian","doi":"10.1136/jitc-2024-010735","DOIUrl":"10.1136/jitc-2024-010735","url":null,"abstract":"<p><strong>Background: </strong>T-cell exhaustion is a major barrier to effective antitumor immunity and limits the efficacy of cancer immunotherapies. This study investigates the role of suppressor of T-cell signaling 2 (STS2, also known as UBASH3A) in regulating CD8⁺ T-cell exhaustion within the tumor microenvironment.</p><p><strong>Methods: </strong>We used genetic ablation of STS2 in mouse models to assess tumor control and responses to anti-programmed cell death protein 1 (PD-1) checkpoint blockade therapy. CD8⁺ tumor-infiltrating lymphocytes (TILs) were characterized through flow cytometry, mass cytometry, and single-cell transcriptomics. Mechanistic studies included co-immunoprecipitation, protein degradation assays, and endocytosis measurements to elucidate the interplay between STS2 and PD-1.</p><p><strong>Results: </strong>STS2 expression progressively increased with T-cell exhaustion. Genetic deletion of STS2 enhanced tumor control and improved responses to anti-PD-1 therapy. STS2-deficient CD8⁺ TILs maintained a more functional state, exhibiting enhanced effector activity, proliferation, and antitumor efficacy while resisting terminal exhaustion. Mechanistically, we discovered that STS2 physically interacts with PD-1 and modulates its expression, endocytosis, and degradation at the protein level.</p><p><strong>Conclusions: </strong>Our findings establish STS2 as a multifaceted regulator of T-cell exhaustion and highlight its potential as a therapeutic target for enhancing antitumor immunity and improving cancer immunotherapy outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475346","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 real-world study on the efficacy and safety of low-dose PD-1 monoclonal antibody alone or in combination as the first-line treatment for advanced non-small cell lung cancer.","authors":"Jingqi Sun, Junli Hao, Xin Li, Lu Xu, Tao Han, Sha Shi, Heming Li, Mingfang Zhao","doi":"10.1136/jitc-2025-011622","DOIUrl":"10.1136/jitc-2025-011622","url":null,"abstract":"<p><strong>Background: </strong>In clinical practice, patients with non-small cell lung cancer (NSCLC) often receive low-dose programmed death-1 (PD-1) monoclonal antibodies due to physical or financial limitations. However, the efficacy and safety of low-dose compared with standard-dose PD-1 monoclonal antibodies remain underexplored.</p><p><strong>Methods: </strong>This retrospective study included 400 patients with locally advanced or advanced NSCLC treated with PD-1 inhibitors as initial systemic therapy, either as monotherapy or combination therapy. Patients were classified into standard-dose (n=216), mid-treatment dose reduction (n=26), and low-dose (n=158) groups. Progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were evaluated. Baseline characteristics were balanced using propensity score matching (PSM) in the combination therapy cohort. Non-inferiority of low-dose therapy for PFS (margin=1.3) and OS (margin=1.33) was based on clinical rationale and previous studies..</p><p><strong>Results: </strong>32 patients (8%) underwent surgery following systemic therapy. Among patients receiving first-line monotherapy (n=25), mPFS was 34.6 months for low-dose (L), 59.8 months for standard-dose (S), and 17.4 months for mid-treatment dose reduction (M), with no significant differences (HR (L vs S) = 0.81, 95% CI: 0.17 to 3.83; HR (M vs S) = 3.91, 95% CI: 0.45 to 34.14; p=0.37). In first-line combination therapy, before PSM, the mPFS was 16.8 vs 12.1 months and mOS was 35.7 vs 42.6 months (L vs S). After PSM, outcomes remained comparable (mPFS: 18.2 vs 11.2 months, p=0.22; mOS: 35.7 vs 28.7 months, p=0.47). Importantly, in the first-line combination therapy cohort, the incidence of grade ≥3 irAEs was significantly lower in the low-dose group (9.7% vs 17.9%, p=0.030). PFS met the non-inferiority criterion after PSM, whereas OS did not, likely due to an insufficient number of events.</p><p><strong>Conclusions: </strong>Low-dose PD-1 monoclonal antibody therapy demonstrated comparable efficacy to standard-dose therapy with a lower incidence of severe irAEs in combination regimens. These findings suggest a cost-effective and safe alternative, warranting validation in future randomized controlled trials.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475329","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":"Correction: Dexmedetomidine induces immunogenic cancer cell death and sensitizes tumors to PD-1 blockade.","authors":"","doi":"10.1136/jitc-2024-010714corr1","DOIUrl":"10.1136/jitc-2024-010714corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333170","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":"Correspondence on \"Early dynamics of clinical and laboratory parameters predict primary refractory disease in patients with metastatic urothelial carcinoma receiving atezolizumab\"by Graser <i>et al</i>.","authors":"Mingzhu Gao, Liwen Zhang, Jinyou Wang","doi":"10.1136/jitc-2025-012582","DOIUrl":"10.1136/jitc-2025-012582","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333172","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":"Response to: Correspondence on \"Early dynamics of clinical and laboratory parameters predict primary refractory disease in patients with metastatic urothelial carcinoma receiving atezolizumab\" by Gao <i>et al</i>.","authors":"Christopher Graser, Thomas O McDonald, Paul J Catalano, Guru Sonpavde, Franziska Michor","doi":"10.1136/jitc-2025-012742","DOIUrl":"10.1136/jitc-2025-012742","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333174","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":"Reciprocal immune-epithelial interaction during breast cancer induction.","authors":"Neil Carleton, Michael T Lotze","doi":"10.1136/jitc-2024-011453","DOIUrl":"10.1136/jitc-2024-011453","url":null,"abstract":"<p><p>The notion of immune editing and its defined phases (elimination, equilibrium, and escape), once a transformed cell emerges, is now well established. What occurs prior to, and may in fact impact, transformation-inflammation, initiation, and inception of malignancy-has been a murkier proposition. These \"three I's\" form the basis of a concept we put forth called reciprocal learning, which we define as a constant crosstalk in non-diseased tissue between the local epithelial cells and immune cells that occurs across the lifespan. Epithelial cells and resident macrophages provide the basis for genetic and epigenetic alterations as a site for learning by adaptive immune cells. Conversely, epithelial cells learn which changes are recognized by both innate and adaptive immune cells by modulating expression of MHC molecules and the antigen processing and presentation machinery. This \"reciprocal learning\" that occurs between the local epithelium and immune system provides memory for the immune system to then respond to dysregulated epithelial growth across the lifespan. We illustrate this with important recent findings of immune cells within the normal breast. An immune response is most certainly present (surveilling) the breast epithelium from the onset of mammary gland development, during active menstrual cycling, during lactation, and in the postmenopausal period with involution. We speculate that this reciprocal learning may be one of the main reasons why seven out of eight women <i>do not</i> get breast cancer in their lifetime.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333173","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":"HVJ-E links Apolipoprotein d to antitumor effects.","authors":"Airi Ishibashi, Noriko Ohta, Yuko Uegaki, Hidefumi Suzuki, Katsuya Fukino, Yuuta Hisatomi, Atsushi Tanemura, Riuko Ohashi, Koji Kitamura, Kotaro Saga, Yasuhide Yoshimura, Satoko Inubushi, Kyoso Ishida, Yoko Ino, Yayoi Kimura, Kenjiro Sawada, Tadashi Kimura, Eiji Kiyohara, Kosuke Yusa, Hidehisa Takahashi, Yasufumi Kaneda, Keisuke Nimura","doi":"10.1136/jitc-2024-011442","DOIUrl":"10.1136/jitc-2024-011442","url":null,"abstract":"<p><strong>Background: </strong>Virotherapy eradicates tumors by directly killing cancer cells and causing adjuvant effects. However, the mechanism by which non-replicating virotherapy exerts anti-tumor effects is unclear.</p><p><strong>Methods: </strong>In this study, we investigated the genes that mediate the anti-tumor effects of ultraviolet (UV)-irradiated Hemagglutinating Virus of Japan envelope (HVJ-E) using RNA sequencing, gene knockout, and a drug-inducible gene expression system. We examined the antitumor effects of Apolipoprotein d (Apod) using genome-wide CRISPR library screening, in situ biotinylation combined with mass spectrometry, flow cytometry, biochemistry, and tumor-bearing mouse models.</p><p><strong>Results: </strong>Here, we show that HVJ-E represses tumor growth via Irf7-induced Apod expression in tumor cells <i>in vivo</i>. Irf7 in B16F10 cells is a pivotal transcription factor for HVJ-E-induced anti-tumor effects. Apod substantially suppresses tumor growth even in HVJ-E-insensitive tumors. Apod is required to increase NKG2D-ligand genes in HVJ-E-treated tumors. Genome-wide CRISPR library screening and <i>in situ</i> biotinylation of Apod reveal an association of Apod with ERK2. Mechanistically, Apod prevents the nuclear translocation of ERK2 and Importin7, increasing NKG2D-ligands expression in B16F10 cells and attenuating tumor growth. Treating a local tumor with a combination therapy of Apod with the anti-OX40, T cell costimulatory molecule, antibody substantially repressed tumor growth in target and non-target lesions alongside T cell activation.</p><p><strong>Conclusion: </strong>Our findings provide insights into the molecular mechanisms of how HVJ-E induces anti-tumor effects and can aid the development of therapeutic strategies for eliciting anti-tumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336594","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":"Correction: Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto's paradox to druggable cancer hallmark.","authors":"","doi":"10.1136/jitc-2024-010486corr1","DOIUrl":"10.1136/jitc-2024-010486corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333171","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}