Cancer immunology research最新文献

{"title":"Close Spatial Interactions between Cancer Cells and Cancer-Associated Fibroblasts Suppress Antitumor Immunity.","authors":"Yuto Naoi, Yumi Inukai, Tomoka Izumikawa, Joji Nagasaki, Takamasa Ishino, Youki Ueda, Yin Min Thu, Miho Fujiwara, Takahiro Baba, Go Makimoto, Ken Suzawa, Kazuhiro Okada, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Shuta Tomida, Yoshinobu Maeda, Shinichi Toyooka, Mizuo Ando, Yosuke Togashi","doi":"10.1158/2326-6066.CIR-24-1144","DOIUrl":"10.1158/2326-6066.CIR-24-1144","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAF) play immunosuppressive roles in the tumor microenvironment. Specifically, they reportedly act as physical barriers preventing immune cell infiltration. However, the spatial relationships between CAFs and cancer cells in antitumor immunity remain unknown. In this study, we established three-dimensional (3D) constructs, in which the spatial relationships were controlled using a 3D bioprinter. Using these models, we found that the mixed distribution of fibroblasts (FB) and cancer cells suppressed the antitumor immunity more than the surrounding distribution of FBs as physical barriers. The 3D construct with mixed distribution promoted TGFβ and periostin (encoded by Postn gene) cross-talk, resulting in immunosuppression. Postn knockdown in FBs decreased the TGFβ production in the mixed 3D construct and activated antitumor immunity both in vitro and in vivo. Clinically, patients with head and neck cancer or lung cancer showing a mixed distribution of α-smooth muscle actin+ myofibroblast-like CAFs exhibited worse prognosis after PD-1 blockade therapies, and lower CD8+ T-cell infiltration than those that had CAFs surrounding cancer cells. Overall, our findings suggest that the close interactions of CAFs and cancer cells facilitate immunosuppression, rather than the physical barriers created by CAFs, highlighting their potential as biomarkers and therapeutic targets for cancer immunotherapies based on spatial relationships. Furthermore, this study highlights the beneficial applications of 3D bioprinters.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1471-1484"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539068","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":"Harnessing Notch Signaling to Enhance the Generation and Functionality of Human Conventional Type 1 Dendritic Cells for Cancer Immunotherapy Applications.","authors":"Sreekumar Balan, Liam O'Brien, Ante Peros, Xuedi Wang, Ingrid Leal Rojas, Christopher McClain, Kristen J Radford, Nina Bhardwaj","doi":"10.1158/2326-6066.CIR-25-0034","DOIUrl":"10.1158/2326-6066.CIR-25-0034","url":null,"abstract":"<p><p>A dendritic cell (DC)-based vaccine, Sipuleucel-T, remains the sole FDA-approved cancer vaccine. Despite their established safety and efficacy against cancers and infections in numerous trials, long-term clinical benefits have been modest. Most trials have employed DCs derived from blood monocytes, but emerging evidence underscores the unique role of conventional type 1 DCs (cDC1) in triggering potent antitumor immune responses and their intratumoral infiltration with favorable prognoses in many cancers. However, the scarcity of cDC1s in peripheral blood and the challenges in generating them in vitro have hindered a deeper understanding of their biology and their widespread application as cellular vaccines. In this study, we present a serum-free culture system capable of generating billions of human cDC1s from CD34+ progenitors derived from cord or peripheral blood. The system leverages the requirement of Notch signaling for cDC1 differentiation and generates DCs that closely resemble in vivo cDC1s, exhibiting functions including cellular antigen cross-presentation. This robust protocol enables the scalable production of cDC1s for both fundamental biological research and therapeutic applications.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1328-1341"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539069","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":"GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma.","authors":"Reona Okada, Jeyshka M Reyes-González, Constanza Rodriguez, Taisuke Kondo, Jangsuk Oh, Ming Sun, Michael C Kelly, Ling Zhang, James Gulley, Jack F Shern, Mitchell Ho, Christian S Hinrichs, Naomi N Taylor, Xiyuan Zhang, Rosa Nguyen","doi":"10.1158/2326-6066.CIR-24-0975","DOIUrl":"10.1158/2326-6066.CIR-24-0975","url":null,"abstract":"<p><p>Neuroblastoma is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in neuroblastoma, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines. However, its systemic toxicity remains an important therapeutic challenge. In this study, we evaluated the efficacy of IL15- and IL21-enhanced glypican 2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden neuroblastoma. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR + sol.IL15.IL21), constitutive membrane-tethered expression (GPC2-CAR + teth.IL15.IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR + NFAT.IL15.IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high neuroblastoma burden xenograft models. Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high neuroblastoma burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR + NFAT.IL15.IL21 exhibited significantly lower anorexia-associated morbidity/mortality. Supporting these data, tumor-infiltrating GPC2-CAR + NFAT.IL15.IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR + teth.IL15.IL21 maintained a proinflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL15/IL21 enhanced GPC2-CAR T-cell function against a high neuroblastoma burden with acceptable tolerability in mice. Further studies are required to validate these findings.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1363-1373"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494728","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":"Tumor-derived EBI3 promotes CD8+ T cell exhaustion via STAT4-IL-10/CCL5 in gastric cancer.","authors":"Yong-Jia Yan, Xin Liu, Daohan Wang, Zexuan Shen, Wenxin Zhang, Zhaoxiong Zhang, Yangpu Jia, Peiyao Wang, Yuman Fong, Yanghee Woo, Weihua Fu","doi":"10.1158/2326-6066.CIR-24-1228","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1228","url":null,"abstract":"<p><p>Combination chemotherapy and immunotherapy are effective against advanced gastric cancer (GC). However, T cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T cell exhaustion and its mechanism in GC, showing high expression of EBI3 in GC. Correlation analysis between EBI3 expression level and clinical-pathological features indicated significant associations with Tumor stage, Nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T cell exhaustion, as identified by transcriptome sequencing and mice orthotopic GC models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in vitro/vivo studies. Mechanistically, EBI3 induced T cell exhaustion by promoting phosphorylation of STAT4, upregulating the transcription of downstream target genes CCL5 and IL-10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T cell exhaustion. Taken together, we identified a T cell exhaustion mechanism in GC via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in GC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943996","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":"Tunneling CARs: Increasing CAR T-cell tumor infiltration through the overexpression of MMP-7 and Osteopontin-b.","authors":"Stacey Van Pelt, Mark White, Candise Tat, Devyn Hooper, Lindsay J Talbot, Mary Kathryn McKenna, Rohan Fernandes, Cliona M Rooney, Bilal Omer","doi":"10.1158/2326-6066.CIR-25-0149","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0149","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy against hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle in solid tumors is the extracellular matrix (ECM), which impedes CAR T-cell infiltration. In clinical trials, neuroblastoma (NB) has shown responsiveness to GD2-directed CAR T-cell therapy, however, the failure of GD2.CAR T cells to effectively clear bulky disease - characterized by dense ECM - highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CAR T cells exhibit a unique infiltration-restriction compared to other CAR T cells and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 (which encodes osteopontin; OPN) as candidate genes to improve the infiltration of GD2.CAR T cells as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CAR T-cell extravasation and interstitial movement in ECM-dense environments in vitro. Overexpression of either OPN or MMP-7 significantly improved tumor infiltration in a xenograft model of NB. This resulted in improved tumor control and a survival extension in OPN-GD2.CAR T-cell treated mice compared to unmodified GD2.CAR T cells. OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CAR T-cell infiltration in solid tumors and identifies OPN as a candidate to explore in this regard.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944048","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":"Spatiotemporal immune landscape and long-term immune memory in POLE-mutant endometrial cancer at the single-cell level.","authors":"Koen Brummel, Marta Requesens, Nienke van Rooij, Hagma H Workel, Florine A Eggink, Annechien Plat, René Wardenaar, Diana C J Spierings, Floris Foijer, David N Church, Joost Bart, Hans W Nijman, Marco de Bruyn","doi":"10.1158/2326-6066.CIR-25-0083","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0083","url":null,"abstract":"<p><p>Polymerase epsilon mutant (POLE-mut) endometrial cancers (EC) are characterized by a near 100% disease-specific survival rate, even when treated by surgery alone. This spectacular survival, combined with the ultramutated genome and high level of neoantigens in these tumors, indicates a substantial degree of immune control in preventing disease spread and recurrence. Although these features are intriguing, the immune infiltration of POLE-mut EC has predominantly been confined to immunohistochemistry studies. Here, we used state of the art single-cell RNA and TCR sequencing to characterize the immune landscape of POLE-mutant ECs. Moreover, we uniquely analyzed patient blood samples taken two to eight years after curative treatment to assess formation of long-term immune memory in circulation. We identified specialized tumor-infiltrating myeloid subsets at different stages of maturation, an array of lymphocytes ranging from immature to cytotoxic and adaptive natural killer (NK) as well as tumor-reactive exhausted and effector T cells, contributing to a highly inflammatory anti-tumor response. Remarkably, our analysis of blood samples taken years after curative treatment uncovered the presence of tumor-reactive T cell clones that matched the primary tumor. This indicates the formation of systemic long-term memory immune responses in POLE-mut EC survivors. Our study highlights the distinctive immunogenicity of POLE-mut EC and identifies key features associated with persistent anti-tumor immunity that may contribute to prolonged, relapse-free survival.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944001","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":"Targeting Myeloid Cells for Cancer Immunotherapy.","authors":"Lucas Blanchard, Andrew Mijacika, Juan C Osorio","doi":"10.1158/2326-6066.CIR-25-0159","DOIUrl":"10.1158/2326-6066.CIR-25-0159","url":null,"abstract":"<p><p>Myeloid cells - including monocytes, macrophages, dendritic cells, and granulocytes - are critical architects of the tumor microenvironment, where they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic, and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944006","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":"IFNγ-induced PD-L1+MHC II+ macrophages and Tim-3+ tumor-reactive CD8+ T cells predict a response to anti-PD-1 therapy in tumor-bearing mice.","authors":"Jelena Gabrilo, Sylvie Vande Velde, Coralie Henin, Sébastien Denanglaire, Abdulkader Azouz, Louis Boon, Benoit J Van den Eynde, Muriel Moser, Stanislas Goriely, Oberdan Leo","doi":"10.1158/2326-6066.CIR-24-0835","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0835","url":null,"abstract":"<p><p>While immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model using P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti-PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade (ICB)-based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. Herein, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 were associated with a positive antitumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and non-responding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHC IIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of non-responding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte to macrophage differentiation route may hamper the response to ICB. These insights will direct future research towards a temporal analysis of tumor-associated macrophages (TAMs), aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way to novel strategies to enhance the efficacy of PD-1 blockade.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944055","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":"Evaluation of proton minibeam radiation therapy on anti-tumor immune responses in a rat model of glioblastoma.","authors":"Lorea Iturri, Miriam Riquelme-Perez, Pierre-Emmanuel Bonté, Sarah Potiron, Christel Goudot, Marjorie Juchaux, Elise Brisebard, Cristèle Gilbert, Julie Espenon, Ramón Ortiz, Annalisa Patriarca, Ludovic De Marzi, Sebastián Amigorena, Yolanda Prezado","doi":"10.1158/2326-6066.CIR-24-0902","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0902","url":null,"abstract":"<p><p>Treating radioresistant tumors like glioblastoma multiforme (GBM) remains a challenge exacerbated by their immunosuppressive nature. Radiation therapy has an immunomodulatory role, both immunosuppressive and immunostimulatory. The nature of the effects depends on the total dose, dose per fraction, dose delivery method and treatment length. Hypofractionation is observed to tip the balance towards immune stimulation. However, the use of hypofractionation is restricted in bulky tumours, i.e. gliomas, due to the high risk of toxicity. Therefore, finding new strategies leading to more favourable immune responses while reducing normal tissue toxicities could improve cancer treatment. Here we examine anti-tumoral immune responses to proton minibeam radiation therapy (pMBRT). However, its immunomodulatory effects are not fully understood. To explore this, we conducted an in-depth characterization of the immune response to a curative dose of pMBRT in a preclinical orthotopic rat model of glioblastoma. Our findings revealed a close association between pMBRT and the immune response. pMBRT increased lymphocyte density in tumors more effectively than conventional proton therapy. Single-cell transcriptomics identified several immune cell types and unique transcriptional changes in tumor immune cells post-pMBRT, including increased antibody production, chemotactic cytokine expression, and interferon responses. These results underscore the critical role of adaptive immunity, specifically T cells, in pMBRT's mechanism. The potential of pMBRT to trigger an anti-tumor immune response in a single radiotherapy session with minimal damage to healthy tissue makes it a promising candidate for future clinical trials and radio-immunotherapy combinations.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943886","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":"Neoadjuvant immunotherapy promotes the formation of mature tertiary lymphoid structures in a remodeled pancreatic tumor microenvironment.","authors":"Dimitrios N Sidiropoulos, Sarah M Shin, Meredith Wetzel, Alexander A Girgis, Daniel Bergman, Ludmila Danilova, Susheel Perikala, Daniel Shu, Janelle M Montagne, Atul Deshpande, James Leatherman, Lucie Dequiedt, Victoria Jacobs, Aleksandra Ogurtsova, Guanglan Mo, Xuan Yuan, Dmitrijs Lvovs, Genevieve Stein-O'Brien, Mark Yarchoan, Qingfeng Zhu, Elizabeth I Harper, Ashani T Weeraratna, Ashley L Kiemen, Elizabeth M Jaffee, Lei Zheng, Won Jin Ho, Robert A Anders, Elana J Fertig, Luciane T Kagohara","doi":"10.1158/2326-6066.CIR-25-0387","DOIUrl":"10.1158/2326-6066.CIR-25-0387","url":null,"abstract":"<p><p>Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Herein, we report the generation of a spatial multi-omics atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning across distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that significantly associated with improved survival in PDAC patients. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854614","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}