Cancer immunology research最新文献

{"title":"Neutrophil Extracellular Traps Modulate Recruitment and Immunosuppression of Macrophages in Pancreatic Adenocarcinoma.","authors":"Hillary G Pratt, Alyson M Stevens, Michael Sestito, Mercy Ojetunde, Abby D Ivey, Nicole E Mihalik, Kayla J Steinberger, Britney Niemann, E Hannah Hoblitzell, Edwin Wan, Timothy D Eubank, Brian A Boone","doi":"10.1158/2326-6066.CIR-24-0534","DOIUrl":"10.1158/2326-6066.CIR-24-0534","url":null,"abstract":"<p><p>Pancreatic adenocarcinoma (PDAC) has a dismal survival rate due to limited effective therapies. Although studies have focused on the influence of innate immune cells on adaptive immune cell functions, few have explored interactions between innate immune cells, which modulate the PDAC tumor microenvironment (TME). Macrophages are responsible for the clearance of neutrophil-mediated inflammation in physiologic, resolving immune responses; however, both of these cell types coexist in the TME, suggesting a failure of macrophages to clear neutrophils in PDAC. We sought to determine how neutrophil extracellular traps (NET), neutrophil release of decondensed chromatin, and intracellular contents affect monocyte/macrophage populations in the PDAC TME. Utilizing samples from patients with PDAC, we demonstrated elevated levels of the monocyte chemokine CCL2 in plasma, as well as elevated NET citrullinated histone H3 and the pan-macrophage marker CD68 in the PDAC TME via fluorescent IHC. To determine how NETs affected macrophage populations in the PDAC TME, we targeted NETs with DNase I treatment to digest extracellular DNA released from NETs or with genetic knockout of PAD4, an enzyme required for NET formation. NET depletion resulted in an elevation in the pan-macrophage marker F4/80. The depletion led to an increased T-cell stimulatory signal, CD80, whereas the protumor macrophage marker CD206 was decreased. We further demonstrated that macrophages in the NET-deficient PDAC TME may be recruited through the CCL2/CCR2 axis, and CCL2 was released from tumor cells and macrophages in the presence of IFNγ. Taken together, our findings reveal that inhibition of NETs can prime the innate immune response toward an antitumor phenotype.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1547-1560"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752499","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":"Spatial Analysis of the Tumor Microenvironment in Diffuse Large B-cell Lymphoma Reveals Clinically Relevant Cell Interactions and Recurrent Cellular Neighborhoods.","authors":"Matias Autio, Suvi-Katri Leivonen, Leo Meriranta, Marja-Liisa Karjalainen-Lindsberg, Teijo Pellinen, Sirpa Leppä","doi":"10.1158/2326-6066.CIR-24-1163","DOIUrl":"10.1158/2326-6066.CIR-24-1163","url":null,"abstract":"<p><p>Recent studies have explored the composition of the tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL) However, cell-to-cell interactions, along with the spatial organization of DLBCL TME and their impact on patient outcomes, have remained poorly characterized. We applied multiplex immunofluorescence, cell phenotyping, and neighborhood analysis to investigate 1,218,756 single cells in 99 samples from patients with primary DLBCL. We identified 17 cell phenotypes and 10 recurrent cellular neighborhoods (RCN) across samples, subdividing DLBCLs into immune-poor areas and areas with diverse immune cell infiltrates. Avoidance of B cells and PD-1+ T cells was associated with less aggressive clinical characteristics and favorable survival. Likewise, the proximity of CD8+ T cell-rich and immune-poor RCNs translated to favorable patient outcomes, and the proximity of PD-L1+ B cell-rich and CD8+ T cell-rich RCNs to unfavorable patient outcomes. Our findings provide insights into the spatial interactions and organization of DLBCL TME with implications for patient outcomes.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1674-1686"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793563","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 Dual Role for NKG7 in T-cell Cytotoxicity and Longevity.","authors":"Haidong Dong, Hyoungjun Ham, Whitney Barham, Ti Wen, Jacob B Hirdler, Zhiming Mao, Dallin S Ashton, Wenjing Zhang, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau","doi":"10.1158/2326-6066.CIR-25-0384","DOIUrl":"10.1158/2326-6066.CIR-25-0384","url":null,"abstract":"<p><p>The effectiveness of T cell-based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell-based immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1510-1515"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871623","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":"Regulatory T Cells Poise the Myeloid Landscape after Chemotherapy in Lung Tumors.","authors":"Eléonore Weber-Delacroix, Marylou Panouillot, Marie Laviron, François Lanthiez, Tristan Philippe, Sandrine Barthélémy, Solène Fastenackels, Armanda Casrouge, Benoit L Salomon, Ingrid Sassoon, Jeremy Baudhuin, Ilaria Onorati, Marianne Kambouchner, Nahla Cucherousset, Christophe Combadière, Boris Duchemann, Marie-Caroline Dieu-Nosjean, Alexandre Boissonnas","doi":"10.1158/2326-6066.CIR-25-0103","DOIUrl":"10.1158/2326-6066.CIR-25-0103","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) and regulatory T cells (Treg) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. Although Tregs are well known for their immunosuppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. In this study, we have shown that in human and mouse lung cancer, chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward not only a proinflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the proinflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the proinflammatory signature of the MPs, and improved survival in the mouse model. Targeting the cross-talk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1561-1575"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552395","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":"A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-13-10-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-13-10-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 10","pages":"1509"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198542","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":"Antibody Mediated Inhibition of HLA/LILR Interactions Breaks Innate Immune Tolerance and Induces Antitumor Immunity.","authors":"Abir K Panda, Kannan Natarajan, Surajit Sinha, Jiansheng Jiang, Sruthi Chempati, Lisa F Boyd, Priyanka P Desai, Maja Buszko, Yong-Hee Kim, Soha Kazmi, Bryan Fisk, Martha E Teke, Carolina M Larrain, Kirsten Remmert, Andrew M Blakely, Iyadh Douagi, Jonathan M Hernandez, David H Margulies, Ethan M Shevach","doi":"10.1158/2326-6066.CIR-25-0343","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0343","url":null,"abstract":"<p><p>Immune check-point blockade for the treatment of malignancies has been focused on reversing inhibitory pathways in T lymphocytes. Natural killer (NK) cells are a potent innate defense against tumors and virally infected cells, but their therapeutic manipulation for anti-cancer immunity has been inadequately explored. Considerable attention has been focused on approaches to blocking inhibitory receptors on NK and myeloid cells. Most effort has been directed to the killer immunoglobulin-like receptors (KIR) and CD94/NKG2A on NK cells. Another set of receptors with similar function in both NK cells and myeloid cells is the leukocyte immunoglobulin like receptors (LILR) that interact with a wide variety of HLA molecules. Using pan-anti-HLA mAbs that recognize a conserved epitopic region on HLA also seen by LILR, we investigated their functional effects in several models of tumor immunity. The pan-anti-HLA-mAbs blocked the binding of most LILRs, did not block killer cell immunoglobulin-like receptors (KIR) or CD94/NKG2A/C or TCR recognition. They also activated dysfunctional NK cells explanted from a variety of human cancers, and resulted in enhancement of tumor immunity in humanized mice. The mAbs also exert direct anti-tumor effects. These results suggest that activation of innate immunity via disruption of HLA/LILR interactions is a potent approach for control of both primary tumors and potentially tumor metastases.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198503","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":"Correction: Inflammation Mediated by Gut Microbiome Promotes Immune Suppression and Lung Adenocarcinoma Progression.","authors":"Zahraa Rahal, Yuejiang Liu, Fuduan Peng, Sujuan Yang, Mohamed A Jamal, Manvi Sharma, Hannah Moreno, Ashish V Damania, Matthew C Wong, Matthew C Ross, Ansam Sinjab, Tieling Zhou, Minyue Chen, Inti Tarifa Reischle, Jiping Feng, Chidera Chukwuocha, Elizabeth Tang, Camille Abaya, Jamie K Lim, Cheuk Hong Leung, Heather Y Lin, Nathaniel Deboever, Jack J Lee, Boris Sepesi, Don L Gibbons, Jennifer A Wargo, Junya Fujimoto, Linghua Wang, Joseph F Petrosino, Nadim J Ajami, Robert R Jenq, Seyed Javad Moghaddam, Tina Cascone, Kristi Hoffman, Humam Kadara","doi":"10.1158/2326-6066.CIR-25-0804","DOIUrl":"10.1158/2326-6066.CIR-25-0804","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1687"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013803","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":"Reprogramming CD8+ T-cell Branched N-Glycosylation Limits Exhaustion, Enhancing Cytotoxicity and Tumor Killing.","authors":"Catarina M Azevedo, Bingxian Xie, William G Gunn, Ronal M Peralta, Carolina S Dantas, Henrique Fernandes-Mendes, Supriya Joshi, Victoria Dean, Pedro Almeida, Drew Wilfahrt, Nuno Mendes, Julian López Portero, Carmen Poves, María Jesús Fernández-Aceñero, Ricardo Marcos-Pinto, Ângela Fernandes, Greg M Delgoffe, Salomé S Pinho","doi":"10.1158/2326-6066.CIR-25-0313","DOIUrl":"10.1158/2326-6066.CIR-25-0313","url":null,"abstract":"<p><p>T-cell therapies have transformed cancer treatment. Although surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell-mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc-branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR-Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted the assessment of whether MGAT5 deletion in anti-CD19 chimeric antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 knockout anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance the antitumor activity of native and CAR T cells.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1655-1673"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871624","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":"Endoglin-Directed CAR T Cells Comprehensively Target Tumors in Advanced Sarcomas.","authors":"Harrison R Berger, Malina Maharana, Jeneffer Mirabal, Lyazat Kurenbekova, Alberto Delaidelli, Atreyi Dasgupta, Ahmed Z Gad, Mohamed F Sheha, Sybrina S Kerr, Ada I Ozcan, Jessica S Morris, Angela M Major, M John Hicks, Mary K McKenna, Ben K Seon, Matthew L Baker, Poul H Sorensen, Meenakshi Hegde, Jason T Yustein, Nabil Ahmed, Sujith K Joseph","doi":"10.1158/2326-6066.CIR-24-0897","DOIUrl":"10.1158/2326-6066.CIR-24-0897","url":null,"abstract":"<p><p>There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their invasiveness, highlighting its potential as a therapeutic target. Accordingly, we designed a second-generation human ENG-targeting CAR molecule signaling through the CD28 endodomain and retrovirally transduced primary human T cells with this CAR. ENG CAR T cells exhibited strong antigen-specific cytokine release, robust proliferation, memory formation, and cytotoxic function against various sarcoma cell lines. Their cytotoxicity remained unaffected by the presence of soluble ENG or its natural ligand, bone morphogenetic protein-9. Furthermore, ENG CAR T cells disrupted multicellular tumor spheroids in vitro, overcoming tumor compactness and the stromal barrier created by cancer-associated fibroblasts, which are critical challenges in sarcoma CAR T-cell therapy. In orthotopic xenograft models of sarcomas, ENG CAR T-cell treatment resulted in control of tumor growth and metastasis, leading to survival extension. In summary, our study describes the involvement of ENG in sarcoma metastasis and validates our human ENG CAR T cells as a potential therapeutic for advanced sarcomas.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1591-1608"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759265","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":"High Levels of Endogenous Omega-3 Fatty Acids Promote Dendritic Cell Antigen Presentation and Improve Dendritic Cell-Based Cancer Vaccine Efficacy in Mice.","authors":"Shweta Tiwary, Kevin S Hsu, Katherine C Goldfarbmuren, Zheng Xia, Jay A Berzofsky","doi":"10.1158/2326-6066.CIR-24-0927","DOIUrl":"10.1158/2326-6066.CIR-24-0927","url":null,"abstract":"<p><p>Antigen presentation by dendritic cells (DC) is crucial in activating T cells. DCs capture, process, and present antigens to T cells, making them attractive vaccine vehicles. However, most DC cancer vaccines have had limited clinical efficacy, suggesting a need to increase their potency. We report that high levels of omega-3 fatty acids in mice significantly prolonged lifespan and reduced tumor growth and body weight loss. This effect was mediated in part by more effective DC antigen presentation. DCs derived from Tg(CAG-fat-1)Jxk/J transgenic mice expressing high omega-3 lipid levels were better vaccine vehicles than wild-type (WT) DCs in treating cancers in WT mice and in stimulating CD8+ T-cell responses in vitro and in vivo. Although no effect on the levels of expression of costimulatory molecules was detected, we discovered a marked enhancement of T-cell dwell time on DCs. We also observed that differentiating DCs from WT bone marrow in the presence of omega-3 lipids increased DC antigen presentation capacity in vitro, suggesting a potential approach to enhance DC-based cancer vaccine efficacy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1609-1622"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774729","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}