Journal for Immunotherapy of Cancer最新文献

{"title":"Gut microbiota derived indole-3-acetic acid ameliorates precancerous inflammatory intestinal milieu to inhibit tumorigenesis through IL-35.","authors":"Juanjuan Wang, Yang Hao, Yazheng Yang, Yuan Zhang, Chen Xu, Rongcun Yang","doi":"10.1136/jitc-2024-011155","DOIUrl":"https://doi.org/10.1136/jitc-2024-011155","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota can significantly alter the risk or progression of cancer by maintaining gut immune system homeostasis. However, the exact mechanism by which the gut microbiota and its metabolites influence colorectal tumorigenesis is unclear.</p><p><strong>Methods: </strong>The roles of tryptophan metabolite indole-3-acetic acid (IAA) in inflammation and tumor development were investigated in dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS mouse models with or without IAA supplementation and with or without <i>Lactobacillus reuteri</i>-produced IAA. Pregnane X receptor (PXR) knockout (KO) mice and aryl hydrocarbon receptor KO mice were used to explore the mechanism by which IAA regulates interleukin (IL)-35 expression. IL-35⁺ immune cells were stimulated in vitro and analyzed by flow cytometry. Additionally, metabolites were analyzed by liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>We found that IAA, a metabolite of tryptophan produced in the gut by <i>L. reuteri</i>, can inhibit the development of colitis by inducing IL-35 expression in immunosuppressant cells. <i>HuREG3α^IECtg</i> mice had high levels of intestinal microbiota-derived IAA, and these mice were resistant to AOM-DSS-induced cancer. Patients with colorectal cancer also had low peripheral blood levels of IAA. Further studies revealed that IAA-producing <i>L. reuteri</i> alleviated colitis symptoms and inhibited colon tumors by inducing macrophages, T cells, and B cells to produce IL-35. Finally, PXR KO completely abolished the effects of IAA on immune cells.</p><p><strong>Conclusion: </strong>We demonstrate that gut microbiota-derived IAA can improve the precancerous colon inflammatory environment through IL-35, thereby inhibiting tumorigenesis, suggesting that IAA may be a preventive factor for colitis-related cancers.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019444","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":"Radiomics in head and neck squamous cell carcinoma - a leap towards precision oncology.","authors":"Pranjal Rai, Abhishek Mahajan","doi":"10.1136/jitc-2025-011692","DOIUrl":"https://doi.org/10.1136/jitc-2025-011692","url":null,"abstract":"<p><p>Immunotherapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, with neoadjuvant chemoimmunotherapy showing promising pathological complete response rates (36-42%). Lin <i>et al</i> introduce a radiomics-clinical nomogram using MRI-derived intratumoral and peritumoral features to predict pCR, addressing a critical clinical gap. Their model, emphasizing the peritumoral region (within 3 mm), achieved high predictive accuracy area under curve (AUC) >0.8. While the multicenter design enhances generalizability, standardizing imaging protocols remains a challenge. Integrating radiomics with the Neck Imaging Reporting and Data System could refine post-treatment assessment. This study advances precision oncology in HNSCC, offering a non-invasive tool for personalized treatment strategies. Future directions include artificial intelligence-driven radiomics and radiogenomics to enhance treatment response prediction and patient selection.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004487","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":"Serum analytes as predictors of disease recurrence and the duration of invasive disease-free survival in patients with triple negative breast cancer enrolled in the OXEL trial treated with immunotherapy, chemotherapy, or chemoimmunotherapy.","authors":"Nicole J Toney, Megan T Lynch, Filipa Lynce, Candace Mainor, Claudine Isaacs, Jeffrey Schlom, Renee N Donahue","doi":"10.1136/jitc-2024-011379","DOIUrl":"10.1136/jitc-2024-011379","url":null,"abstract":"<p><strong>Background: </strong>The OXEL study (NCT03487666) was a phase II trial of patients with triple negative breast cancer (TNBC) with residual disease following neoadjuvant chemotherapy, randomized to receive immunotherapy (anti-programmed cell death protein 1, nivolumab), chemotherapy (capecitabine), or chemoimmunotherapy. We previously reported on the primary endpoint of the OXEL trial, demonstrating that a peripheral immunoscore based on circulating immune cells reflecting immune activation was increased in patients treated with immunotherapy. However, compared with cell-based immune assays, sera assays are more cost-effective, less labor-intensive, and samples easier to obtain. Here, we report on differences in serum analytes between treatment arms and associations with clinical response.</p><p><strong>Methods: </strong>Patients (n=38) were assayed for 97 serum analytes before and after 6 and 12 weeks of therapy. Serum analytes were assessed for changes with therapy, and as predictors of disease recurrence and the duration of invasive disease-free survival (iDFS) in both single analyte analyses and machine learning models.</p><p><strong>Results: </strong>Levels of specific analytes at baseline and changes in levels at early time points on treatment preceding recurrence were associated with eventual development of disease recurrence and/or the duration of iDFS. These associations varied based on the therapy patients received. Immunotherapy led to enrichment in pro-inflammatory analytes following treatment, whereas chemotherapy resulted in overall decreases. Changes seen in patients receiving chemoimmunotherapy more closely resembled those observed in patients receiving immunotherapy alone as opposed to chemotherapy alone. Furthermore, logistic regression and Cox proportional hazard models, developed using machine learning methods, demonstrated that combinations of serum analytes were more predictive of disease recurrence and iDFS duration than analyses of single serum analytes. Notably, the multivariable models that predicted patient outcomes were highly specific to the class of treatment patients received.</p><p><strong>Conclusions: </strong>In patients with TNBC with residual disease after neoadjuvant chemotherapy, treatment with immunotherapy alone or chemoimmunotherapy resulted in enhanced immune activation compared with chemotherapy alone as measured by changes in serum analyte levels. Distinct serum analytes, both at baseline and as changes after therapy, predicted clinical outcomes for patients receiving immunotherapy alone, chemotherapy alone, or chemoimmunotherapy.</p><p><strong>Trial registration number: </strong>NCT03487666.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024537","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":"Reversible downregulation of HLA class I in adenoid cystic carcinoma.","authors":"Annie Li, Bianca L Gonda, Elizabeth M Codd, Adam von Paternos, Dawn R Mitchell, Markus D Herrmann, Prinjali Kalyan, Samantha E Flynn, Thuc Q Dzu, Chengzhuo Gao, Edwin Zhang, Julia J Mendel, Julia C Thierauf, Peter M Sadow, Thomas Denize, Diane Yang, Florian J Fintelmann, Jo Anne Fordham, Ross D Merkin, Atul K Bhan, Yu-Chung Huang, Jeffrey Raizer, William C Faquin, Daniel L Faden, Xin Gao, Jong Chul Park, Lori J Wirth, Stefan T Kaluziak, A John Iafrate","doi":"10.1136/jitc-2024-011380","DOIUrl":"https://doi.org/10.1136/jitc-2024-011380","url":null,"abstract":"<p><strong>Background: </strong>Adenoid cystic carcinoma (ACC) is a rare, but lethal cancer with low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite extensive clinical trials, no effective treatments for patients with recurrent or metastatic ACC are available, and ACC mortality rates remain poor.</p><p><strong>Methods: </strong>We employed automated multiplex immunofluorescence (mIF), single-cell RNA sequencing (scRNA-seq) Gene Expression analysis, RNA in-situ hybridization, and spatial transcriptomics analysis to characterize the immune landscape of ACC tumors, ACC metastasis, and normal tissues from regions where ACCs arise. Based on results from these studies, we treated freshly resected ACCs with interferon-γ or a stimulator of the interferon genes (STING) agonist in vitro. Additionally, we included one patient with ACC in a phase 1 clinical study of a novel STING agonist (dazostinag) plus pembrolizumab.</p><p><strong>Results: </strong>The mIF analysis revealed that ACC tumors are immunologically \"cold\", with few tumor-infiltrating T-lymphocytes and low programmed death-ligand 1 (PD-L1) expression. The most striking finding was a very low beta-2-microglobulin (B2M) expression in nearly all ACCs, with only focal expression found in some ACC metastases. mIF and RNA sequencing analyses of normal salivary gland and breast tissues revealed a p63+, NFIB+, basal duct cell population, with similarly low B2M/human leukocyte antigen (HLA) class I expression. Spatial transcriptomics analysis of the focally B2M-positive ACC metastases uncovered the genetic pathway driving upregulation of B2M, an interferon-γ program mediating the reintroduction of HLA-I/B2M; the significantly upregulated genes included <i>IRF1, GBP1,</i> and <i>TAP1</i>. On short-term treatment of primary ACC tissues in vitro with interferon-γ or a STING agonist, we observed strongly upregulated HLA class I/B2M expression. Moreover, treatment of a patient with recurrent, metastatic breast ACC with a STING agonist and pembrolizumab led to a partial response with a 70% tumor reduction.</p><p><strong>Conclusions: </strong>Low B2M/HLA class I expression may explain why ACCs are immunologically cold and the lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in a B2M/HLA-class I low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, as supported by the promising response observed in a patient with metastatic ACC. These findings indicate a potential path to urgently needed immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004490","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":"Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies.","authors":"Cristina Bayó, Giancarlo Castellano, Fátima Marín, Joaquín Castillo-Iturra, Teresa Ocaña, Hardeep Kumari, Maria Pellisé, Leticia Moreira, Liseth Rivero, Maria Daca-Alvarez, Oswaldo Ortiz, Sabela Carballal, Rebeca Moreira, Julia Canet-Hermida, Marta Pineda, Capella Gabriel, Georgina Flórez-Grau, Manel Juan, Daniel Benitez-Ribas, Francesc Balaguer","doi":"10.1136/jitc-2024-011177","DOIUrl":"https://doi.org/10.1136/jitc-2024-011177","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such strategies. Cancer vaccines targeting FSDNs offer a promising approach for immune interception in LS. This study aimed to identify and validate LS-related FSDNs to develop vaccines for cancer prevention.</p><p><strong>Methods: </strong>We identified LS-related coding MS mutations and predicted FSDN with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles. We validated FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples from patients with LS, non-LS tumors, and cell lines. Immunogenicity was assessed through interferon (IFN)-γ enzyme-linked immunospot and flow cytometry analysis of tissue-infiltrating lymphocytes (TILs) from LS carriers.</p><p><strong>Results: </strong>We prioritized 53 HLA-I and 45 HLA-II FSDNs in MSI tumors using in silico predictions. Validation revealed 86.7% of FSDN-associated mutations present in LS-CRC samples, with a median of 7.67 (6.5-9) mutations in CrADs and 6.02 (2-10) in CRCs. Sequencing of CrAD and EC samples showed 95% and 77.5% of predicted FSDN-associated mutations, respectively. MSI cancer cell lines transcribed 69.8% of FSDNs. Immunogenicity assays showed that 71% of potential FSDNs elicited IFN-γ responses, with a median of 7.37 (1-10.75) HLA-I and 6 (2-5.75) HLA-II FSDNs per patient. After prioritizing 24 FSDN, in a cohort of 19 LS-derived samples (4 CrAD and 15 normal mucosa), 52% (10/19) demonstrated T-cell reactivity to an HLA-I neoantigen pool. CD8+CD137+ activation markers increased significantly (p=0.037) over time and peptide-specific cells were detected by pentamer staining.</p><p><strong>Conclusions: </strong>Our predicted FSDN set has optimal coverage among LS carriers and can induce IFN-γ inflammatory responses in LS-derived TILs, offering an opportunity for vaccine development.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990673","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":"MARC, a novel modular chimeric antigen receptor, improves T cell-based cancer immunotherapies by preventing early T cell exhaustion and enhancing persistence.","authors":"Margaux Tual, Angélique Bellemare-Pelletier, Susan Moore, Delphine Guipouy, Negar Farzam-Kia, Leila Jafarzadeh, Jordan Quenneville, Benoit Barrette, Marc K Saba-El-Leil, Jean-Sebastien Delisle, Etienne Gagnon","doi":"10.1136/jitc-2025-011829","DOIUrl":"https://doi.org/10.1136/jitc-2025-011829","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor T cell (CAR-T)-based immunotherapies have reshaped the therapeutic landscape of cancer treatment, in particular for patients afflicted with leukemia. However, defects in CAR behaviors and clinical complications have hindered their widespread application across diverse cancer types. Chief among these defects is high tonic signaling, absent in native activating immune receptors, which accelerates T cell exhaustion and undermines treatment efficacy. We hypothesized that these limitations arise because current CAR architectures fail to replicate the modular design of native activating immune receptors, which integrate distinct receptor and signaling modules. This modular assembly is crucial for maintaining proper receptor regulation and function.</p><p><strong>Methods: </strong>Therefore, we set forth to develop a modular chimeric antigen receptor leveraging the same assembly principles found in native activating immune receptors to reestablish the intrinsic safeguards in receptor expression and signaling.</p><p><strong>Results: </strong>The resulting Modular Actuation Receptor Complex (MARC) displayed surface expression levels akin to its native immune receptor counterpart, the NK cell receptor KIR2DS3, while eliminating tonic signaling. In a clinically relevant mouse leukemia model, MARC-T cells exhibited remarkable long-term persistence and a less exhausted phenotype compared with conventional CAR-T cells.</p><p><strong>Conclusions: </strong>With its modular architecture, the MARC offers unparalleled opportunities for optimization and broad applicability across different cell types, paving the way for transformative advancements in cell-based therapies. This innovation holds immense promise as a next-generation therapeutic tool in clinical settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018826","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":"CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy.","authors":"Regina M Myers, Amanda M DiNofia, Yimei Li, Caroline Diorio, Hongyan Liu, Gerald Wertheim, Joseph A Fraietta, Vanessa Gonzalez, Gabriela Plesa, Donald L Siegel, Emma Iannone, Laura Shinehouse, Jennifer L Brogdon, Clare Taylor, Julie K Jadlowsky, Elizabeth O Hexner, Boris Engels, Diane Baniewicz, Colleen Callahan, Marco Ruella, Richard Aplenc, Allison Barz Leahy, Susan E McClory, Susan R Rheingold, Lisa Wray, Carl H June, Shannon L Maude, Noelle V Frey, Stephan A Grupp","doi":"10.1136/jitc-2025-011549","DOIUrl":"https://doi.org/10.1136/jitc-2025-011549","url":null,"abstract":"<p><strong>Background: </strong>Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed.</p><p><strong>Methods: </strong>We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS).</p><p><strong>Results: </strong>Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1-2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone.</p><p><strong>Conclusions: </strong>The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies.</p><p><strong>Trial registration numbers: </strong>NCT02650414 and NCT03620058.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004479","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":"Past failures and new horizons: the nuances of tertiary lymphoid structures in high-grade serous ovarian cancer may contribute to immunotherapy effectiveness.","authors":"Rufiaat Rashid, Lan Coffman, Tullia C Bruno, Ian MacFawn","doi":"10.1136/jitc-2025-011670","DOIUrl":"https://doi.org/10.1136/jitc-2025-011670","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that allow for optimal B-T cell crosstalk in solid tumors. Further, TLS are found in many solid tumors and are associated with improved patient survival and superior immunotherapeutic response, ultimately reflecting their potential as new therapeutic targets. Despite the prognostic benefit of TLS, women with high-grade serous ovarian cancer (HGSOC) are insensitive to immunotherapies. We have summarized recent work on TLS in patients with HGSOC, ultimately demonstrating how tumor microenvironment factors and therapeutics shape the organization and maturation of TLS. Specifically, TLS function varies across anatomical sites, with more germinal center (GC)+TLS with active B cells found in tumors within the omentum and fallopian tube compared with ovary. Further, cancer-associated stromal cells within patients negate the prognostic benefit of TLS and reduce B cell recruitment and function with blunted differentiation of follicular dendritic cells, which lay the foundation for functional GCs. Neoadjuvant chemotherapy (NACT) also impacts the HGSOC microenvironment, with metastatic tumors showing increased infiltration of effector immune cells (primarily TCF1+PD1+ CD8+ T cells) and \"mature\" TLS formation compared with NACT-naïve patients. These findings provide a rationale for designing therapeutics targeting the HGSOC TLS landscape and restoring immunotherapeutic responses in these patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012537","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":"Single-cell RNA sequencing of human double-negative T cells reveals a favorable cellular signature for cancer therapy.","authors":"Enoch Tin, Ismat Khatri, Karen Fang, Yoosu Na, Michele Nawata, Juan Arteaga, Mark D Minden, Sergio Rutella, Jongbok Lee, Li Zhang","doi":"10.1136/jitc-2024-010684","DOIUrl":"https://doi.org/10.1136/jitc-2024-010684","url":null,"abstract":"<p><strong>Background: </strong>Allogeneic double-negative T-cell (DNT) therapy has emerged as a novel, off-the-shelf cellular treatment with clinical feasibility, safety, and promising efficacy against leukemia. However, the biology of DNTs is less well characterized, and how DNT therapy distinguishes from conventional γδ T-cell therapy remains unclear. Collectively, this hinders our ability to bolster DNT functionalities in cancer therapy. Here, we performed single-cell RNA sequencing with in vitro and in vivo functional analysis on DNTs. As a significant proportion of DNTs express Vγ9Vδ2 (Vδ2) TCR chain, we compared DNTs with donor-matched conventional Vδ2 T cells expanded with zoledronic acid.</p><p><strong>Methods: </strong>Healthy donor-derived allogeneic DNTs and Vδ2 T cells were expanded ex vivo. Single-cell RNA sequencing analysis was performed on both cellular products to identify the transcriptional landscape and inferred cellular interactions within DNTs, followed by comparisons with donor-matched Vδ2 T cells. Unique cellular subsets found only in DNTs were depleted to identify their contributions to the overall efficacy of DNTs against acute myeloid leukemia. The anti-leukemic activity and in vivo persistence of DNTs and Vδ2 T-cells were explored using flow cytometry-based cytotoxicity assays, memory phenotyping, and xenograft models.</p><p><strong>Results: </strong>Despite a shared Vδ2 expression between cellular products, we identified unique cellular compositions in DNTs that contribute to distinct transcriptional and cellular communication patterns relative to the donor-matched Vδ2 T cells, including higher expression of genes identified in chimeric antigen receptor T cells that persist in patients with durable cancer-remission. Vδ2^- DNTs exhibited strong persistence characteristics, and their presence promoted the cytotoxic capabilities of Vδ2⁺ DNTs in repeated stimulation assays. This unique genetic signature and diverse cellular composition of DNTs resulted in better overall ex vivo expansion, prolonged persistence, and superior anti-leukemic activity compared with Vδ2 T cells in vitro and in vivo.</p><p><strong>Conclusions: </strong>These results highlight the unique transcriptional, cellular, and functional profile of human DNTs and support the continued clinical investigation of allogeneic DNT therapy. The data also provide a reference gene signature that may help improve the efficacy of other types of allogeneic adoptive cellular therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026132","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":"Shp-1 regulates the activity of low-affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition.","authors":"Joseph G Matous, Jeremy P Snook, Nico A Contreras, Andrew G Ramstead, Krystal R Charley, Elizabeth M Kolawole, Jacob N Kisiolek, Kaitlyn A Flint, Ashleigh J Soedel, Breyana Robinson, Anaiya B Mendoza, Yohichi Kumaki, Brian D Evavold, Matthew A Williams","doi":"10.1136/jitc-2024-010879","DOIUrl":"https://doi.org/10.1136/jitc-2024-010879","url":null,"abstract":"<p><strong>Background: </strong>The presence of activated CD8 T cells in the tumor microenvironment is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominantly targets high-affinity T cells, which may be less abundant in tumors with few neoantigens. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp-1) in combination with ICI lowers the T cell activation threshold and enhances the ability of low-affinity T cells to mount a productive antitumor response.</p><p><strong>Methods: </strong>In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low-affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice and, on tumor establishment, administered an inhibitor of Shp-1 (TPI-1) with or without ICI treatment. We analyzed treatment-dependent changes in the immune infiltrate in the tumor via flow cytometry, major histocompatibility complex (MHC) tetramer-mediated detection of tyrosinase-related protein 2 (TRP-2)_180-188-specific T cells and a micropipette-based two-dimensional affinity assay to measure the T cell receptor (TCR) affinity.</p><p><strong>Results: </strong>Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector and reduced exhaustion characteristics. In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2_180-188. We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity.</p><p><strong>Conclusions: </strong>We conclude that approaches for altering TCR signaling threshold are effective in enhancing the antitumor response of low-affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neoantigens are not available to drive antitumor responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965238","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}