Journal for Immunotherapy of Cancer最新文献

{"title":"Analysis of treatment-free survival of patients with advanced melanoma receiving nivolumab as monotherapy or in combination with relatlimab in RELATIVITY-047.","authors":"Meredith M Regan, Paolo A Ascierto, Evan J Lipson, Jennell Palaia, Andriy Moshyk, Abraham Selvan, Christopher D Lao, Michael B Atkins, David F McDermott, Ravi Potluri, Sandip Ranjan, Sandeep Bilthare, Georgina V Long, F Stephen Hodi, Hussein Tawbi, Dirk Schadendorf","doi":"10.1136/jitc-2025-012747","DOIUrl":"https://doi.org/10.1136/jitc-2025-012747","url":null,"abstract":"<p><strong>Background: </strong>Treatment-free survival (TFS; time spent free of systemic anticancer therapy) is increasingly used to support traditional endpoints. TFS was previously evaluated in patients with advanced melanoma treated with nivolumab plus ipilimumab. This analysis compared TFS for nivolumab plus relatlimab and nivolumab monotherapy in patients with advanced melanoma.</p><p><strong>Methods: </strong>Data were from 714 patients in the phase 2/3 RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). TFS was defined as the difference in restricted mean event times between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic anticancer therapy initiation or death. TFS was further partitioned into time with and time without grade ≥3 treatment-related adverse events (TRAEs). Subgroup analysis based on tumor <i>BRAF</i> mutational status and tumor programmed death ligand 1 (PD-L1) expression level was conducted. Between-treatment group differences were calculated with bootstrapped 95% CIs.</p><p><strong>Results: </strong>At 48 months from randomization, Kaplan-Meier estimates of overall survival were 52% and 43% for patients in the nivolumab plus relatlimab and nivolumab groups, respectively; 38% and 33% of patients in these respective groups were free of subsequent systemic therapy. The 48-month mean TFS was 2.9 months (95% CI 1.0 to 4.9) longer with nivolumab plus relatlimab than with nivolumab (9.7 vs 6.8 months, respectively). Mean TFS represented 20% and 14% of the 48-month period after initiating nivolumab plus relatlimab and nivolumab, respectively. Considering only time without grade ≥3 TRAEs, the 48-month mean TFS was 2.6 months (95% CI 0.8 to 4.5) longer with nivolumab plus relatlimab than with nivolumab (9.1 vs 6.5 months, respectively). The 48-month mean total TFS was consistently longer with nivolumab plus relatlimab than with nivolumab in the <i>BRAF</i> mutant (9.4 vs 6.5 months), <i>BRAF</i> wild-type (9.9 vs 6.9 months), PD-L1 ≥1% (12.3 vs 7.7 months), and PD-L1<1% (7.9 vs 6.2 months) subgroups.</p><p><strong>Conclusions: </strong>This analysis demonstrated TFS benefit during the 48 months since initiating nivolumab plus relatlimab compared with nivolumab alone in patients with advanced melanoma. A direct comparison between nivolumab plus relatlimab and nivolumab plus ipilimumab is needed to determine the differences between the regimens in TFS and those in traditional endpoints.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053435","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":"Genome editing or small molecule inhibition of KMT5A in CAR-T cells enhances antitumor immunity.","authors":"Xiaoling Tian, Guolong Liu, Qiudao Wang, Na Zhang, Yanting Shen, Bing Du, Yuxuan Wu","doi":"10.1136/jitc-2025-012160","DOIUrl":"https://doi.org/10.1136/jitc-2025-012160","url":null,"abstract":"<p><strong>Background: </strong>Adoptive T-cell therapy has emerged as a promising therapeutic strategy for cancer treatment. However, clinical challenges persist, including the limited ability of CD8+T cells to infiltrate solid tumors and efficiently eliminate tumor cells. Given the critical role of epigenetic mechanisms in antitumor immunity, targeting epigenetic regulators represents a critical step toward optimizing adoptive T-cell therapies for solid tumors.</p><p><strong>Methods: </strong>To investigate the role of <i>KMT5A</i> in CD8+T cell function, we employed CRISPR screening to identify <i>KMT5A</i> as a negative regulator. We then genetically deleted <i>KMT5A</i> in human CD8+T cells and systematically evaluated its impact on the antitumor efficacy of chimeric antigen receptor (CAR)-T cells using xenograft models. Furthermore, we used the small-molecule inhibitor UNC0379 to pharmacologically inhibit KMT5A, meticulously assessing the consequent effects on CAR-T cell activation, cytotoxicity, and antitumor activity.</p><p><strong>Results: </strong>We report that lysine methyltransferase <i>KMT5A</i> acts as a negative regulator of CD8+T cell function, identified via CRISPR screening. <i>KMT5A</i> deletion in human CD8+T cells significantly enhances the antitumor efficacy of CAR CD8+T cells in xenograft models. In vitro immunophenotyping reveals that <i>KMT5A</i> deletion improves effector functions, cytokine secretion, and early activation of CD8+T cells. Mechanistically, <i>KMT5A</i> depletion increases the expression and chromatin accessibility of multiple effector-related genes in CD8+T cells. KMT5A-mediated histone H4 modifications and chromatin remodeling suppress CD8+T cell effector functions, partially via inhibition of the transcription factor <i>SP1</i>. Notably, pharmacological inhibition of KMT5A using the small-molecule inhibitor UNC0379 enhanced activation, cytotoxicity, and antitumor activity in human CD8+T cells-a novel finding in this study.</p><p><strong>Conclusions: </strong>Our findings establish <i>KMT5A</i> as an epigenetic regulator that impairs CD8+T cell function. These findings demonstrate that genetic or pharmacological (eg, UNC0379) targeting of <i>KMT5A</i> in CD8+T cells represents a viable therapeutic strategy to augment effector functions and improve adoptive T-cell therapies, particularly CAR-T cells, for solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053394","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":"Novel circulating microRNA signature for early detection and prognostication of checkpoint inhibitor-related pneumonitis.","authors":"Haiyi Deng, Yi Yang, Yilin Yang, Ying Liang, Fei Wang, Lanmengxi Yang, Kangjing Ma, Junyi Mo, Zekun Chenli, Junwei Wu, Yuheng Liu, Jin Su, Liqiang Wang, Shiyu Su, Yinxiao Xia, Zirui Wang, Xinyi Wu, Ni Sun, Wenhui Guan, Xinqing Lin, Xiaohong Xie, Yao Liao, Chengzhi Zhou, Lifu Wang","doi":"10.1136/jitc-2025-012270","DOIUrl":"https://doi.org/10.1136/jitc-2025-012270","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint inhibitor-related pneumonitis (CIP) represents a highly lethal immune-related adverse event. Early diagnosis of CIP is crucial for timely intervention and improved prognosis; however, the absence of precise and effective diagnostic techniques often leads to underdiagnosis and misdiagnosis. This study aims to identify microRNA (miRNA) features from serum and extracellular vesicles (EVs) for the early CIP detection and prognosis.</p><p><strong>Methods: </strong>Small RNA sequencing identified candidate miRNAs in 27 serum-derived EV samples from persons with lung cancer and CIP (CIP group) and those without, including immunotherapy-treated persons with lung cancer without CIP (immune checkpoint inhibitor, ICI group) and patients with infectious pneumonia (PNE group). These miRNAs were validated in EV samples in a discovery cohort (n=48) using a quantitative reverse transcription-PCR (qRT-PCR). Diagnostic models for the biomarkers were developed using a training cohort (ICI:47, PNE:28, CIP:31) and validated in a separate validation cohort (ICI:32, PNE:19, CIP:21) using qRT-PCR in both EV and serum samples, and logistic regression. Using a Cox regression model, we built a prognostic risk stratification for patients with CIP based on three miRNAs.</p><p><strong>Results: </strong>Sequencing analysis initially screened and identified 13 overexpressed miRNAs in patients with CIP. Subsequently, qRT-PCR demonstrated that three miRNAs (EVs miR-193a-5p, serum miR-193a-5p, and serum miR-378a-3p) effectively distinguished CIP from non-CIP individuals (training cohort: area under the curve (AUC)=0.870; validation cohort: AUC=0.837). Notably, this miRNA signature was equally robust in differentiating CIP from ICI (training cohort: AUC=0.823; validation cohort: AUC=0.845) and PNE groups (training cohort: AUC=0.892; validation cohort: AUC=0.907). Furthermore, when combined with lymphocyte levels, the miRNA signature significantly enhanced the overall diagnostic accuracy in distinguishing CIP from the non-CIP group (training cohort: AUC=0.900; validation cohort: AUC=0.932), and maintained its robustness in distinguishing CIP from the ICI group (training cohort: AUC=0.898; validation cohort: AUC=0.946) and the PNE group (training cohort: AUC=0.938; validation cohort: AUC=0.959). Additionally, the three-miRNA panel was independently and significantly associated with overall survival in patients with CIP (HR: 2.827; p=0.040).</p><p><strong>Conclusions: </strong>Our circulating miRNA-based signature represents a non-invasive and robust diagnostic tool for patients with CIP and could accurately predict their prognosis. This signature may facilitate early detection and personalized management of these patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053531","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":"Mapping the cancer vaccine landscape.","authors":"Fang Hu, Huan Li, Weiran Lv, Mengjing Li, Robert Peter Gale, Xiaojun Huang, Yang Liang","doi":"10.1136/jitc-2025-012505","DOIUrl":"https://doi.org/10.1136/jitc-2025-012505","url":null,"abstract":"<p><p>The incidence of cancer globally is increasing, predominantly because of an aging population and bringing with it substantial challenges. Cancer vaccines are based on the premise that there are unique features of a cancer or agents causing a cancer which are recognizable by the immune system. Cancer vaccines can be classified as preventive and therapeutic. We searched Trialtrove and identified 2100 clinical trials of cancer vaccine published January 1, 2000 to November 1, 2024, numbers of trials have been explosive growth since 2008: 37% were phase-1, 21%, phase-1/phase-2, 32%, phase-2, 2%, phase-2/phase-3, 5%, phase-3 and 1%, phase-4. Most studies are in the USA (45%). 1% were in infants, 5% in children, and 94% on adults. The most common cancer studied is non-small-cell lung cancer (N=298; 12%) followed by melanoma (N=277; 11%). In conclusion, the research of cancer vaccines is rapidly advancing, particularly in therapeutic cancer vaccines. An increasing number of multicenter clinical trials of cancer vaccines are being initiated globally, and these efforts hold significant promise for bringing hope to patients with cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053458","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":"Innate and adaptive immune features associated with immune-related adverse events.","authors":"Shaheen Khan, Venkat S Malladi, Mitchell S von Itzstein, Hong Mu-Mosley, Farjana J Fattah, Yang Liu, Mary E Gwin, Jason Y Park, Suzanne M Cole, Sheena Bhalla, Jay Lohrey, David Hsiehchen, Angela Moses, Tao Wang, Yaming Xue, Angela B Mobley, J David Farrar, Marjaan Imam, Michelle Wu, Quan-Zhen Li, Edward K Wakeland, Yang Xie, Jeffrey A SoRelle, David E Gerber","doi":"10.1136/jitc-2025-012414","DOIUrl":"https://doi.org/10.1136/jitc-2025-012414","url":null,"abstract":"<p><strong>Background: </strong>While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potentially severe immune-related adverse events (irAEs), underscoring the need to understand irAE biology.</p><p><strong>Methods: </strong>We used a multidimensional approach incorporating single-cell RNA sequencing, mass cytometry, multiplex cytokine assay, and antinuclear antibody (ANA) profiling to characterize the peripheral immune landscape of patients receiving ICI therapy according to irAE development.</p><p><strong>Results: </strong>Analysis of 162 patients revealed that individuals who developed clinically significant irAEs exhibited a baseline proinflammatory, autoimmune-like state characterized by a significantly higher abundance of CD57⁺ T and natural killer (NK) T cells, plasmablasts, proliferating and activated CXCR3⁺ lymphocytes, CD8⁺ effector and terminal effector memory T cells, along with reduced NK cells and elevated plasma ANA levels. In irAE cases, we identified distinct baseline proinflammatory gene signatures, including markedly higher expression of <i>IL1B</i> and <i>CXCL8</i> in monocytes and <i>CXCR3</i>, <i>TNF</i>, and <i>IFNG</i> in T/NK cells. TNF signaling was the most enriched pathway, while immunosuppressive genes <i>SIGLEC7</i> and <i>CXCR4</i> were downregulated. Following ICI initiation, these patients exhibited an enhanced shift toward an activated and inflammatory immune phenotype, including monocyte reprogramming characterized by upregulation of <i>IL18</i> and elevated gene expression levels of <i>CXCL10</i>. Conversely, post-treatment levels of CXCL8 were decreased in irAE patients. Notably, in patients who did not develop clinically significant irAE, we identified increased baseline abundance of a TGFBI^high myeloid cluster enriched in immunosuppressive markers such as <i>STAB1</i>. In addition, patients without irAE exhibited upregulation of TNF and AIRE, accompanied by distinct myeloid protumorigenic reprogramming.</p><p><strong>Conclusions: </strong>A pre-existing activated, autoimmune-like proinflammatory state drives the development of irAE during ICI therapy through three key axes: increased plasmablast/ANA, heightened interferon-gamma/CXCL10/CXCR3 axis, and amplified TNF signaling. These findings may serve as potential peripheral immune biomarkers for predicting irAE and provide biological insights into the mechanisms governing and mitigating irAE.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033385","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":"Factors that increase class I MHC expression may contribute to the development of immune checkpoint inhibitor-induced diabetes.","authors":"Lilach Aizenbud, Noam Savion Gaiger, Ana Luisa Perdigoto, Jacqueline E Mann, Madeline Candelas Torres, Genevieve M Boland, Aleigha R Lawless, Shahar Silverman, David Aaron Schoenfeld, Jodhel I Destina, Nitzan Hasson, Thuy Tran, Michael Hurwitz, Matthew R Austin, Ryan J Sullivan, Kevan C Herold, Harriet M Kluger","doi":"10.1136/jitc-2025-012358","DOIUrl":"https://doi.org/10.1136/jitc-2025-012358","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have improved survival of patients with cancer, yet they pose risks of immune-related adverse events (irAEs). ICI-induced insulin-dependent diabetes mellitus (ICI-DM) is a life-threatening and life-altering irAE. Previously, we reported a high incidence of a germline missense variant in <i>NLRC5</i>, a key class I transcription activator, among patients with ICI-DM compared with similarly treated patients who did not develop ICI-DM. Our purpose was to validate this finding in additional ICI-treated patients and study effects of the <i>NLRC5</i> variant on expression of class I major histocompatibility complex (MHC) antigen presentation genes.We assessed the prevalence of the C>T missense variant at chr16:57 025 515 (<i>NLRC5Pro191Leu</i>) in germline DNA from an additional 33 patients with ICI-DM and in patients with ICI-induced colitis (n=15), ICI-induced hypothyroidism (n=19) and ICI-induced hypophysitis (n=17). The 1,000 Genomes Project was used for comparison. We assessed peripheral blood mononuclear cells from 16 individuals with or without the <i>NLRC5</i> variant, studying expression of <i>NLRC5</i> and select downstream target genes, before and after stimulation with interferon-γ.We validated the higher prevalence of <i>NLRC5Pro191Leu</i> in a non-overlapping cohort of patients with ICI-DM compared with the general population (51.5% vs 12.8%, p<0.0001). The prevalence of <i>NLRC5Pro191Leu</i> in ICI-induced colitis or thyroiditis patients did not significantly differ from the general population, while the prevalence in ICI-induced hypophysitis was somewhat higher (21.6%, p=0.048). We found greater increases in messenger RNA expression of <i>NLRC5</i> (p=0.007), <i>TAP1</i> (p=0.0002), <i>B2M</i> (p=0.0005), <i>HLA-G</i> (p=0.04), <i>PSMB8</i> (p=0.03) and <i>PSMB9</i> (p=0.01) in <i>NLRC5Pro191Leu</i> cells stimulated with interferon-γ compared with <i>NLRC5^WT</i> cells. A similar trend was observed for <i>HLA-A</i> (p=0.09).We confirm the significantly higher prevalence of the <i>NLRC5Pro191Leu</i> variant in patients with ICI-DM relative to the general population. This abundance appears to be unique to patients who develop ICI-DM or hypophysitis on ICIs, underscoring its potential involvement in the pathogenesis of these endocrinopathies. The effects of this <i>NLRC5</i> variant on class I MHC regulators suggest a mechanistic connection between the variant and development of ICI-DM. Further work is warranted to determine whether class I MHC molecules can be modulated in patients with the <i>NLRC5Pro191Leu</i> variant requiring ICIs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040138","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":"Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and <i>Akkermansia muciniphila</i> to regulate gut microbial metabolite 5-HIAA.","authors":"Shilong Sun, Longhao Wang, Kang Cui, Yuchao Ding, Yujie Wei, Yuanyuan Zheng, Zhibo Shen, Lili Zhu, Yaqi Yang, Pu Yu, Yiqiong Song, Ke Chao, Yixing Zhang, Yahao Ge, Wenxuan Ji, Chunwei Li, Gautam Sethi, Lifeng Li, Jie Zhao","doi":"10.1136/jitc-2025-011831","DOIUrl":"10.1136/jitc-2025-011831","url":null,"abstract":"<p><strong>Background: </strong>Improving the efficacy of anti-programmed death 1 (PD-1) monoclonal antibody (mAb) therapy remains a major challenge for cancer immunotherapy in non-small cell lung cancer (NSCLC). Gut microbial metabolites can influence immunotherapy efficacy.</p><p><strong>Methods: </strong>ELISA was used to compare the serum 5-hydroxyindoleacetic acid (5-HIAA) level in patients with NSCLC. Humanized mice were constructed to observe the effect of 5-HIAA on immunotherapy. RNA-seq and flow cytometry were used to analyze the effect of 5-HIAA on tumor-infiltrating lymphocytes. The effects of phenelzine (Phe) and <i>Akkermansia muciniphila</i> (<i>AKK</i>) on 5-HIAA synthesis, antitumor immunity and immunotherapy efficacy were analyzed. Finally, the synergistic effect of Phe combined with <i>AKK</i> on anti-PD-1 mAb was observed.</p><p><strong>Results: </strong>Here we found that 5-HIAA, which is regulated by gut microbiota, has increased concentrations in the serum of non-responders to immunotherapy. Supplementation of 5-HIAA inhibited the efficacy of anti-PD-1 mAb and tumor infiltration of CD8⁺ T cells. The use of monoamine oxidase inhibitor (MAO-I) Phe inhibited the synthesis of 5-HIAA, then improved the efficacy of anti-PD-1 mAb. In addition, supplementation of <i>AKK</i> can also decrease 5-HIAA in serum. Finally, the combination of Phe and <i>AKK</i> maximally inhibited 5-HIAA synthesis and improved immunotherapy efficacy.</p><p><strong>Conclusions: </strong>Our investigations reveal that alterations in gut microbial composition leading to increased 5-HIAA synthesis can negatively impact CD8⁺ T cell functionality and the success of immunotherapy. The combination of Phe and <i>AKK</i> supplementation holds potential for optimizing immunotherapy efficacy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033368","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":"High MGMT expression identifies aggressive colorectal cancer with distinct genomic features and immune evasion properties.","authors":"Janie Yue Zhang, Barani Kumar P Rajendran, Shruti S Desai, Joanna Gibson, Jassim DiPalermo, Patricia LoRusso, Yong Kong, Hongyu Zhao, Michael Cecchini, Kurt A Schalper","doi":"10.1136/jitc-2025-011653","DOIUrl":"https://doi.org/10.1136/jitc-2025-011653","url":null,"abstract":"<p><strong>Introduction: </strong>The epigenetic silencing of O⁶-methylguanine DNA methyltransferase (<i>MGMT</i>) is associated with reduced DNA repair capacity, carcinogenesis and increased sensitivity to alkylating chemotherapy. However, the biological role and clinical significance of MGMT overexpression in cancer remains poorly understood.</p><p><strong>Methods: </strong>Using multiplexed quantitative immunofluorescence we measured the localized levels of MGMT protein, γH2AX and CD8+ T cells in multiple retrospective colorectal cancer (CRC) cohorts. Genomic and transcriptomic features of selected cases were also studied with whole exome DNA sequencing and genome-wide methylation analysis. <i>MGMT</i>-methylated human CRC cells SW620 were transfected with an <i>MGMT</i>-containing plasmid and co-cultured with allogeneic peripheral blood mononuclear cells.</p><p><strong>Results: </strong>A subset of CRCs showed MGMT protein upregulation associated with lower γH2AX, reduced CD8+ tumor infiltrating lymphocytes (TILs), mismatch repair proficient (pMMR) status and shorter survival. CD8+ TILs were more distant from MGMT-expressing cells than MGMT-negative cells and the MGMT promoter methylation status did not highly correlate with MGMT protein levels in CRC. In genomic/transcriptomic analysis, high MGMT expression was associated with a lower nonsynonymous somatic mutational burden, higher transition-to-transversion mutation ratio, increased deleterious <i>TP53</i> variants and distinct transcriptomic profiles. The exogenous expression of MGMT in SW620 CRC cells reduced the number of spontaneous nonsynonymous mutations, reproduced mutational features of MGMT-high CRC and limited the in vitro T-cell-mediated killing of malignant cells induced by proinflammatory cytokines in tumor/immune cell co-cultures.</p><p><strong>Conclusions: </strong>MGMT overexpression identifies a previously undescribed subset of CRCs with distinct biological and clinical properties including reduced mutagenesis, adaptive immune evasion, predominantly pMMR phenotype and aggressive clinical course. Direct, quantitative assessment of MGMT protein expression using spatially resolved analysis is more reliable than inference of MGMT expression by promoter methylation status in CRC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040155","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":"Artificial intelligence in medical imaging empowers precision neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma.","authors":"Jia Fu, Xiaoying Huang, Mengjie Fang, Xin Feng, Xu-Yao Zhang, Xuebin Xie, Zhuozhao Zheng, Di Dong","doi":"10.1136/jitc-2025-012468","DOIUrl":"10.1136/jitc-2025-012468","url":null,"abstract":"<p><p>Neoadjuvant immunochemotherapy (nICT) has demonstrated significant potential in improving pathological response rates and survival outcomes for patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, substantial interindividual variability in therapeutic outcomes highlights the urgent need for more precise predictive tools to guide clinical decision-making. Traditional biomarkers remain limited in both predictive performance and clinical feasibility. In recent years, the application of artificial intelligence (AI) in medical imaging has expanded rapidly. By incorporating voxel-level feature maps, the combination of radiomics and deep learning enables the extraction of rich textural, morphological, and microstructural features, while autonomously learning high-level abstract representations from clinical CT images, thereby revealing biological heterogeneity that is often imperceptible to conventional assessments. Leveraging these high-dimensional representations, AI models can provide more accurate predictions of nICT response. Future advancements in foundation models, multimodal integration, and dynamic temporal modeling are expected to further enhance the generalizability and clinical applicability of AI. AI-powered medical imaging is poised to support all stages of perioperative management in ESCC, playing a pivotal role in high-risk patient identification, dynamic monitoring of therapeutic response, and individualized treatment adjustment, thereby comprehensively advancing precision nICT.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033374","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":"Allele-specific HLA LOH in solid tumors: distinct patterns by tumor type and potential prognostic relevance.","authors":"Tomasz Sewastianik, Christian Roy, Michael V Gormally, Meagan Montesion, Patrick Halvey, Aastha Jindal, Hubert Lam, Adam Schoenfeld, Christopher A Klebanoff, Gregory J Opiteck, Dirk Nagorsen","doi":"10.1136/jitc-2025-012435","DOIUrl":"10.1136/jitc-2025-012435","url":null,"abstract":"<p><p>T-cell receptors (TCRs) recognize antigens derived from fragments of somatically expressed proteins that are degraded by the proteasome and presented by specific human leukocyte antigen (HLA) molecules. Recent therapeutic advances using the TCR as a tumor-targeting moiety have focused attention on <i>HLA</i> loss of heterozygosity (LOH) as a potential resistance mechanism. Allele-specific LOH, rather than allele-agnostic, is particularly pertinent, but rarely evaluated. Using a real-world dataset comprising 78,418 cases, we demonstrate that allele-specific LOH occurs at a relatively low frequency (<10%) across all patients with cancer. We observed a modest increase in allele-specific <i>HLA</i> LOH in cancers harboring associated neoantigen driver mutations (eg, <i>KRAS</i> or <i>TP53</i> mutations), but the overall frequency remained consistently low. Furthermore, using an orthogonal dataset, we integrated clinical outcomes with <i>HLA</i> LOH and identified distinct impacts on overall survival in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) cohorts. For instance, <i>A*02:01</i>-specific LOH was linked to worse survival in CRC (HR 0.5355, 95% CI 0.2991 to 0.9589, p=0.0094) but showed a trend toward improved survival in NSCLC (HR 1.249, 95% CI 0.7778 to 2.005). These findings underscore the relevance of allele-specific <i>HLA</i> LOH assessments and reveal nuanced differences in its clinical implications, which should be accounted for in the optimization of TCR-based immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033357","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}