Cancer immunology research最新文献

{"title":"Induction Serplulimab and Chemotherapy Followed by Chemoradiotherapy for Bulky Unresectable Stage III NSCLC: A Phase II Study (SUCCEED-01).","authors":"Chengxin Liu, Yang Du, Dan Han, Baosheng Li, Xiaomeng Liu, Bingjie Fan, Hongfu Sun, Chengrui Fu, Longyu Xu, Tianyuan Dai, Wei Huang","doi":"10.1158/2326-6066.CIR-25-1194","DOIUrl":"10.1158/2326-6066.CIR-25-1194","url":null,"abstract":"<p><p>Patients with bulky, unresectable stage III non-small cell lung cancer (NSCLC) face poor outcomes with standard concurrent chemoradiotherapy (cCRT) due to large radiation fields and toxicity risks. We evaluated the feasibility and efficacy of induction immunochemotherapy to downstage tumors prior to cCRT. In this single-arm, phase II study, eligible patients received two cycles of induction serplulimab plus chemotherapy. Patients without progression underwent multidisciplinary restaging to receive either cCRT with serplulimab consolidation or surgery. The primary endpoints were objective response rate (ORR) after cCRT and changes in lung volume receiving ≥20 Gy (V20). Forty-nine patients were enrolled (75.5% stage IIIB/IIIC). Following induction, the V20 value was significantly reduced by 11.41% (P < 0.001). The ORR following cCRT was 77.14% (95% confidence interval, 59.86%-89.58%). The 12-month progression-free survival and overall survival rates were 76.15% and 90.54%, respectively. Notably, six patients successfully underwent R0 resection, with five achieving a pathologic complete response. Grade 3 adverse events occurred in 14.29% of patients, and toxicities were manageable. Induction serplulimab-chemotherapy prior to cCRT is a promising strategy for bulky, stage III NSCLC. This approach significantly reduced radiation volumes, achieved high response rates, and enabled curative surgery in selected patients with manageable toxicity.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1035-1044"},"PeriodicalIF":7.9,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580445","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 Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-14-6-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-14-6-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"14 6","pages":"899"},"PeriodicalIF":7.9,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944453","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":"Coexpression of IL15 Promotes Effector Differentiation and Sustained Proliferative Capacity in ALPPL2-Specific Human CAR T Cells.","authors":"David Cunningham, Junquan Liu, Inci Cevher Zeytin, David A de la Cerda, Nisha Ghatwai, Amy N Courtney, Linjie Guo, Purva Rathi, Cathy Qizhi Yao, Ningyan Zhang, Zhiqiang An, Andras Heczey","doi":"10.1158/2326-6066.CIR-25-0609","DOIUrl":"10.1158/2326-6066.CIR-25-0609","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells have robust antitumor activity against hematologic malignancies and have the potential to benefit patients with solid tumors. Immune recognition of murine proteins expressed in adoptively transferred T cells and the lack of homeostatic cytokines in the tumor microenvironment can limit the expansion and persistence of CAR T cells. CARs generated only from human sequences could reduce the risk of immune-mediated rejection, and interleukin 15 (IL15), which promotes T-cell survival and fitness, may improve the expansion and persistence of CAR T cells. In this study, we report a CAR construct (ABBz) assembled from human sequences including a single-chain variable fragment (scFv) specific to alkaline phosphatase, placental-like 2 (ALPPL2). This binder was selected through an unbiased, high-throughput screen of a human antibody-derived, phage-displayed scFv library based on binding specificity, stringency, and low dissociation constant. We demonstrated specificity to the antigen, effective cytolytic function, and cytokine production in ABBz T cells. We showed NK-like effector differentiation with sustained proliferative capacity specific to secreted IL15 coexpression in ABBz T cells. Lastly, we demonstrated that ABBz CAR T cells had robust antitumor activity, which was further enhanced through IL15 coexpression, resulting in NK-like effector differentiation with increased cytotoxicity and superior expansion capacity due to reduced apoptosis of CAR T cells. These results demonstrate that IL15 coexpression can promote effector differentiation while maintaining the proliferative capacity of huALPPL2-CAR T cells and provide a foundation for further clinical development of IL15-coexpressing huALPPL2-CAR T cells in patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"933-943"},"PeriodicalIF":8.2,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490720","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":"Loss of miR-29a/b1 Cluster Reprograms the Tumor Microenvironment and Contributes to Immunosuppression in Lung Cancer.","authors":"Natalie K Horvat, Myritney Saint-Cloud, Raihaanah Bint Abdullah Muslim, Yanhua Tian, B Leticia Rodriguez, Margaret A Hall, Alireza Labani-Motlagh, Lixia Diao, Jing Wang, Gregory B Lesinski, Richard A Moffitt, Don L Gibbons, Jessica M Konen","doi":"10.1158/2326-6066.CIR-25-1060","DOIUrl":"10.1158/2326-6066.CIR-25-1060","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI), including those that block PD-1/PD-L1, have revolutionized therapy for patients with non-small cell lung cancer. However, most patients demonstrate no clinical benefit or acquire resistance, even when tumors express PD-L1. This highlights the critical need to dissect tumor survival dependencies to overcome resistance. Using our Kras/p53-driven lung cancer models that demonstrate acquired or intrinsic resistance to ICIs, we performed single-cell RNA sequencing (scRNA-seq) and focused on predicted upstream regulators of differentially expressed genes in the malignant cell cluster of resistant tumors. We found that the micro-RNA miR-29 was downregulated in tumors with anti-PD-1 resistance and that this was associated with significant upregulation of a multitude of miR-29 targets. Furthermore, we found that expression of Enpp2/ATX, a gene encoding an immunosuppressive molecule, was modulated due to miR-29 loss. Reexpression of miR-29 in anti-PD-1-resistant models reduced ATX expression in tumor cells, diminished the fibrotic microenvironment, and increased CD8+ T-cell infiltration. These alterations promoted response to ICIs in an anti-PD-1-resistant model by rewiring the tumor-immune microenvironment, specifically through increased CD8+ T-cell infiltration, reduction of suppressive Ly6C+ monocytes, and a concomitant increase in proinflammatory macrophages. Additional analysis of publicly available RNA-seq data revealed that tumors from patients with lung adenocarcinoma with high miR-29 had increased CD8A and decreased CD14 expression and broad enrichment in immunoregulatory pathways. Together, these data provide evidence that the miR-29 family regulates the tumor microenvironment, including antitumor immune-related pathways in lung cancer, through control of ATX among other target genes, with implications for ICI response.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"974-991"},"PeriodicalIF":7.9,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13034170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147289365","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":"VSIG4 Restricts Hepatocellular Carcinoma Control by Suppressing Tumor-Specific CD8+ T-cell Immunity in the Tumor Microenvironment.","authors":"Jinglong Guo, Siddheshvar Bhela, Monica Sharma, Giulia Protti, Shiuh-Ming Luoh, Siyue Wang, Natalie S Firmino, Dragos C Dasoveanu, Caleb Chan, Veronica Ibarra-Lopez, Conrad Foo, Rajiv Jesudason, Sandra Rost, Tina Scholl, James Ziai, Laetitia Comps-Agrar, Yulei Wang, Sören Müller, Andrey S Shaw, Jing Li, Shannon J Turley, Wenxian Fu","doi":"10.1158/2326-6066.CIR-25-0836","DOIUrl":"10.1158/2326-6066.CIR-25-0836","url":null,"abstract":"<p><p>Immunotherapies have revolutionized the treatment of hepatocellular carcinoma (HCC), yet their response rates remain limited, highlighting the need for new therapeutic targets. In this study, we found that V-set and immunoglobulin domain-containing 4 (VSIG4) is predominantly expressed by macrophages in both mouse and human HCC, with high VSIG4 expression correlating with poor prognosis in patients with HCC. In autochthonous HCC models, VSIG4 deficiency in mice promoted tumor-specific CD8+ T-cell abundance, intratumoral infiltration, and effector function in the tumor microenvironment, resulting in better tumor control and significantly enhanced efficacy of anti-PD-L1 and anti-VEGF combination treatments. Furthermore, we observed that VSIG4+ macrophages colocalize with CD8+ T cells in HCC and that VSIG4 directly mediates T cell suppression in ex vivo and in vitro studies. These findings suggest that VSIG4 is a critical inhibitor of antitumor immunity in HCC and may be targeted for improved immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"718-732"},"PeriodicalIF":7.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282345","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":"CLK1 Promotes Myeloid-Derived Suppressor Cell Trafficking and Reprograms the Tumor Microenvironment by Activating Hippo/YAP Signaling in Colorectal Cancer.","authors":"Peisi Li, Yumo Xie, Dawang Zhou, Xuan Li, Qishan Liu, Ziming Li, Xiaoxia Liu, Jinxin Lin, Meijin Huang, Qian Yan, Yanxin Luo, Huichuan Yu, Xiaolin Wang","doi":"10.1158/2326-6066.CIR-25-0766","DOIUrl":"10.1158/2326-6066.CIR-25-0766","url":null,"abstract":"<p><p>Colorectal cancer is a highly heterogeneous malignancy characterized by complex interactions between tumor cells and the immune system. The tumor microenvironment (TME) plays a crucial role in colorectal cancer progression and response to therapy. However, the mechanisms regulating TME composition remain poorly understood because of the genetic and phenotypic diversity of tumor cells. In this study, we investigated the tumor-intrinsic factors contributing to TME formation and evaluated genotype-based combination strategies to enhance the efficacy of immunotherapy in colorectal cancer. Using RNA sequencing, single-cell analysis, and immunohistochemistry (IHC), we identified pro-oncogenic proteins associated with low immune activation. Functional studies using in vitro co-culture systems, subcutaneous colorectal tumor models, flow cytometry, and IHC revealed a role for CDC-like kinase 1 (CLK1) in tumor progression and immunosuppressive TME remodeling. Mechanistically, CLK1 activation led to hyperactivation of the Hippo signaling pathway, promoting nuclear translocation of Yes-associated protein (YAP) and subsequent transcriptional upregulation of the chemokine CXCL1. Elevated CLK1 expression correlated with increased infiltration of myeloid-derived suppressor cells (MDSC) and impaired antitumor immune responses. Knockdown (KD) of CLK1 significantly reduced MDSC recruitment and restored CD8+ T-cell activity. Moreover, combined CLK1 KD and anti-PD-1 therapy enhanced intratumoral CD8+ T-cell infiltration to a greater extent and elicited robust antitumor responses in murine colorectal cancer models. Collectively, our findings identify the CLK1-Hippo/YAP-CXCL1 signaling axis as a regulator of immune evasion and TME remodeling in colorectal cancer and highlight the potential of therapeutically targeting this axis to improve the efficacy of immune checkpoint blockade.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"875-891"},"PeriodicalIF":7.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178069","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":"Intratumoral Tertiary Lymphoid Structures Characterized by a B Cell-Related Signature Elicit Antitumor Effect through HAPLN3 in Hepatocellular Carcinoma.","authors":"Qianwen Zeng, Yujun Liu, Jingying Chen, Qiaoyi Chen, Zebin Chen, Liting Peng, Zhijuan Li, Kai Lei, Xiaoxuan Lin, Shijia Liu, Ruiyan Xuan, Ruiming Liang, Zhihang Chen, Chuankai Zhang, Changyi Liao, Youmei Kang, Tianhong Su, Shuling Chen, Ming Kuang, Junbin Liao, Jianping Guo, Li Tan","doi":"10.1158/2326-6066.CIR-25-0758","DOIUrl":"10.1158/2326-6066.CIR-25-0758","url":null,"abstract":"<p><p>The existence of intratumoral tertiary lymphoid structures (TLS) has been reported to be correlated with reduced recurrence of hepatocellular carcinoma (HCC). However, the cellular characteristics and driving mechanisms of TLSs in HCC remain largely unknown. In this study, we compared the clinical outcomes of TLSs in HCC using whole-exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing on a cohort of 339 patients with HCC belonging to different TLS groups. Intratumoral TLSs were significantly associated with improved recurrence-free survival in HCC (P = 0.00013), with higher maturity of TLSs correlating with better prognosis (P = 0.00033). A B cell-related seven-gene signature effectively predicted TLS presence (area under the curve = 0.78) and patient prognosis, outperforming previously reported signatures, which were validated in situ by spatial transcriptomic data. Bulk and single-cell transcriptomic analyses revealed that TLS-positive (TLS+) tumors were immunologically active and strongly associated with immunotherapy response signatures. IgG-producing plasma cells, identified as key effector subsets enriched in TLS+ tumors, exhibited clonal expansion, somatic hypermutation, and high-affinity antibody production. Among potential tumor-enriched TLS-associated genes, HAPLN3 was overexpressed in TLS+ HCC and induced high serum antibody titers (P = 0.0032). Spatial transcriptomics and in vivo experiments confirmed that HAPLN3 promotes B-cell activation, leading to suppressed tumor growth. Administration of HAPLN3 protein displayed immunostimulatory and antitumor effects in an orthotopic mouse model. These findings reveal that targeting TLS-associated B-cell responses or leveraging HAPLN3-specific immunity may offer therapeutic avenues for improving immunotherapy outcomes in HCC. See related Spotlight, p. 716.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"771-791"},"PeriodicalIF":7.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147289421","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":"The Presence of CD11c+ B Cells with Potent Effector Memory Phenotype in Lung Adenocarcinoma Correlates with Overall Patient Survival.","authors":"Sharmila Sambanthamoorthy, Yan Ren, Tatiana K Galvez, Benjamin King, Scot D Liu, Brian A Kidd, Debbie A Law, Nicole Baumgarth","doi":"10.1158/2326-6066.CIR-25-0635","DOIUrl":"10.1158/2326-6066.CIR-25-0635","url":null,"abstract":"<p><p>Tumor-infiltrating B lymphocytes (TIL-B) are increasingly recognized as favorable prognostic markers in multiple cancer types, and the mechanisms underlying this are being actively investigated. In this study of TIL-Bs, we identified CD79A as a reliable quantifier of B lymphocytes and evaluated transcriptomic data for 15 distinct tumors using 8,720 samples of treatment naïve patients from The Cancer Genome Atlas and normal tissues from Gene Tissue Expression. B-lymphocyte infiltration correlated with survival for some but not all tumors. In lung adenocarcinoma (LUAD), CD79A levels were strongly predictive of overall survival, whereas CD8A transcripts were not, indicating that leukocytic infiltration per se does not explain the B cell's impact. Single-cell RNA sequencing and flow cytometry identified increased relative numbers of CD11c+ B cells in patients with treatment-naïve LUAD compared with normal tissue and blood. In LUAD, CD11c+ TIL-Bs were localized near CD4+ T cells, and in vitro stimulation with anti-IgG with/without CD40 agonist resulted in expansion and rapid differentiation. Stimulation also induced IL12, IL21, and TNFα secretion, which are cytokines known to enhance antitumor immunity. Overall, the data indicate that CD11c+ TIL-Bs are a potential target for anticancer therapeutic approaches and/or a potential prognostic biomarker for cancer prognosis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"811-826"},"PeriodicalIF":7.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177295","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 Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-14-5-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-14-5-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"14 5","pages":"715"},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811291","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":"Engineered CCR7 Overexpression Enhances Nodal CAR T-cell Homing and Cytotoxicity toward B-cell Lymphoma.","authors":"Maria Zschummel, Mario Bunse, Anna-Lena Spierling, Anna Li, Jara J Joedicke, Anca Margineanu, Susanne Blachut, Eric Lars-Helge Lindberg, Jorge Ruiz-Orera, Norbert Hübner, Armin Rehm, Uta E Höpken","doi":"10.1158/2326-6066.CIR-25-1381","DOIUrl":"10.1158/2326-6066.CIR-25-1381","url":null,"abstract":"<p><p>Anti-CD19 chimeric antigen receptor (CAR) therapy demonstrated remarkable efficacy against hematologic malignancies. However, B-cell malignancies with lymph node (LN) involvement frequently remain resistant. In this study, we show that CAR T cells downregulated the chemokine receptor CCR7, crucial for nodal homing, during manufacturing. Consequently, in vitro migration toward the respective chemokines and in vivo migration to LNs was severely impaired. To improve nodal CAR T-cell trafficking, we engineered anti-CXCR5 CAR T cells, targeting mature lymphoma, with stable CCR7 expression (CAR.CCR7). CCR7 engineering of human and mouse CAR T cells restored migratory capacity and LN homing. Additionally, we observed enhanced CAR-mediated killing in CCR7-engineered anti-CXCR5 and anti-CD19 CARs alike, a process that was independent of increased cytokine secretion. Mechanistically, CCR7 overexpression was associated with an altered expression of genes involved in cytoskeletal rearrangement and faster killing kinetics. CCR7 accumulated in mature CAR synapses, supporting the costimulatory role of CCR7 within immunologic synapses. Therapeutically, improved LN recruitment and enhanced killing of CAR.CCR7 T cells improved lymphoma eradication in mice.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"827-844"},"PeriodicalIF":7.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281833","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}