Oncoimmunology最新文献

{"title":"A dual diacylglycerol kinase (DGK) alpha/zeta inhibitor augments the activity of human tumor infiltrating lymphocytes in <i>in vivo</i> and <i>ex vivo</i> models.","authors":"Phurin Areesawangkit, Karen Pei-Yi Fong, Emma Niemeyer, Yan Li, Kelly Markowitz, Devora Delman, Ryan Krause, Justine Carl, Pat Feldman, Lisa Troung, Rodrigo Hess, Xiaodi Ren, Cynthia Timmers, Sunkyu Kim, Robert Brody, Sunil Singhal, Jarrod Predina, Evgeniy Eruslanov, Gregory Beatty, Bihui Melidosian, Steven M Albelda","doi":"10.1080/2162402X.2025.2608439","DOIUrl":"10.1080/2162402X.2025.2608439","url":null,"abstract":"<p><p>Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied <i>in situ</i> in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2608439"},"PeriodicalIF":6.5,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145851153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA prime and peptide boost immunization elicits robust neoantigen-specific CD8 ⁺ T cell responses and therapeutic protection in mouse tumor models.","authors":"Pablo Morgado-Cáceres, Francisca Hofmann-Vega, Diego Figueroa, Juan Saavedra-Almarza, Felipe Gálvez-Cancino, Ximena Díaz, Evelyn Menares, Eduardo Roa, Sofia Hidalgo, Manuel Varas-Godoy, Vincenzo Borgna, Alvaro Lladser","doi":"10.1080/2162402X.2025.2606497","DOIUrl":"10.1080/2162402X.2025.2606497","url":null,"abstract":"<p><p>Therapeutic immunization against tumor neoantigens has the potential to induce potent and highly selective CD8⁺ T-cell-mediated antitumor immunity. Consequently, immunization strategies that generate robust neoantigen-specific T-cell responses are needed. Here, we tested homologous and heterologous DNA- and peptide-based immunization strategies using a neoantigen model. We observed that priming with DNA followed by peptide boost immunization elicited the strongest CD8⁺ T-cell responses, which exhibited effector and memory precursor phenotypes and led to the formation of circulating and skin-resident memory T cells. In prophylactic settings, this immunization regimen delayed the growth of B16F10 melanoma and rejected EL4 lymphoma cells expressing a self-antigen. In a therapeutic setting, a DNA prime-peptide boost eliminated EL4 tumors expressing the neo-epitope model in most mice. Consistently, DNA prime-peptide boost targeting two bona fide neoepitopes of MC38 tumor model elicited neoepitope-specific CD8⁺ T-cell responses and a marked therapeutic effect, which may be enhanced by combining with anti-PD-1 antibody. These results highlight the potential of DNA prime-peptide boost as a promising strategy for therapeutic neoantigen immunization that elicits strong CD8⁺ T-cell responses and potent antitumor effects.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2606497"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12802984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring dendritic cell migration: a gut reaction to boost vaccine efficacy in aging.","authors":"Liwei Zhao, Oliver Kepp, Guido Kroemer, Peng Liu","doi":"10.1080/2162402X.2026.2657070","DOIUrl":"10.1080/2162402X.2026.2657070","url":null,"abstract":"<p><p>Aging impairs vaccine responses. Dai et al. reported that defective cDC2 migration in immunized old mice, diminishing humoral and cellular immunity. Oral yeast-derived nanoparticles restore DC migration and vaccine efficacy. These findings establish impaired DC migration as a key mechanism of age-related immune decline, introducing a noninvasive strategy to correct immunosenescence.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2657070"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reshaping immunotherapy sequencing strategy: equivalent survival with induction plus consolidation vs. consolidation-only strategy in unresectable stage III NSCLC.","authors":"Wenlu Chen, Anqi Zhao, Yu Liang, Xin Cao, Baixue Wu, Yuying Zhou, Wenbo Zhang, Meng Zhao, Qing Hou, Ningning Yao, Feng Li, Jianchun Duan, Shuangping Zhang, Nan Bi, Jianzhong Cao","doi":"10.1080/2162402X.2026.2670221","DOIUrl":"10.1080/2162402X.2026.2670221","url":null,"abstract":"<p><strong>Objective: </strong>To compare the efficacy and safety of a sequential combination of chemoradiotherapy (CRT) with immune checkpoint inhibitors (ICIs) administered as induction plus consolidation versus consolidation-only in patients with unresectable stage III non-small cell lung cancer (NSCLC).</p><p><strong>Methods: </strong>This retrospective study enrolled 265 patients treated at two centers between March 2019 and August 2023. Patients were categorized into a consolidation-only group (<i>n</i> = 153) and an induction plus consolidation group (<i>n</i> = 112). Propensity score matching (PSM, 1:1 ratio) was used to balance baseline characteristics. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis and log-rank tests. Adverse events (AEs) were evaluated according to CTCAE v5.0.</p><p><strong>Results: </strong>Before PSM, no significant survival differences were observed between groups (2-y PFS: 52.6% vs. 63.5%, <i>p</i> = 0.085; 2-y OS: 91.7% vs. 81.2%, <i>p</i> = 0.822). After PSM, outcomes remained comparable (2-y PFS: 56.8% vs. 62.2%, <i>p</i> = 0.179; 2-y OS: 94.9% vs. 87.9%, <i>p</i> = 0.514). Before PSM, the most common AE was pneumonitis (60.7% vs. 55.1%, <i>p</i> = 0.442). The induction plus consolidation group showed a lower incidence of anemia (<i>p</i> = 0.004) but a higher incidence of ALT/AST elevation (14.3% vs. 5.1%, <i>p</i> = 0.022). The incidence of all other AEs was comparable (<i>p</i> > 0.05). After PSM, only anemia was significantly higher in the consolidation-only group (52.8% vs. 27.8%, <i>p</i> = 0.004).</p><p><strong>Conclusion: </strong>In treatment-tolerant patients, induction plus consolidation therapy demonstrated comparable efficacy and safety to consolidation-only therapy in unresectable stage III NSCLC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2670221"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147949913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models.","authors":"Nuri Sung, Eunsu Kim, Yosef Gilad, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han","doi":"10.1080/2162402X.2026.2640261","DOIUrl":"10.1080/2162402X.2026.2640261","url":null,"abstract":"<p><p>Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8⁺, CD4⁺, and natural killer (NK) immune cells into the tumor microenvironment (TME). Given the anti-tumor effects of SRC-3KO Tregs in two different solid cancers, we sought to extend our studies to additional cancer types. Here, we showed that SRC-3KO Tregs exerted a potent antitumor immunity-like effect, capable of eradicating glioblastoma, melanoma, and lung cancer in their respective syngeneic mouse models by generating an anti-tumor immune environment. These results support the translational development of SRC-3-targeted Treg modulation as a safe and effective immunotherapy platform for treatment-refractory cancers.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2640261"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning based on CD3 histological slides for prediction of colon cancer outcome: analysis of three international stage III colon cancer cohorts.","authors":"Julie Lécuelle, Caroline Truntzer, Debora Basile, Luigi Laghi, Luana Greco, Alis Ilie, David Rageot, Titouan Huppé, Jean-François Emile, Fréderic Bibeau, Julien Taïeb, Valentin Derangère, Come Lepage, François Ghiringhelli","doi":"10.1080/2162402X.2026.2668797","DOIUrl":"10.1080/2162402X.2026.2668797","url":null,"abstract":"<p><p>Prognostic stratification in stage III colon cancer remains poor, despite treatment advances. Tumor-infiltrating lymphocytes, particularly CD3+ T cells, are potential prognostic markers, but manual assessment is labor-intensive and not robust. This study aimed to develop a deep learning model for automated analysis of CD3-stained histological slides to improve prognostic prediction. A total of 1737 patients from three international cohorts (PETACC08, PRODIGE-13, and HARMONY) were analyzed. The deep learning model (VGG19) identified tumor core (TC) and invasive margin (IM) regions on CD3-stained slides. Features from VGG19 and UNI models were used to cluster patients using hierarchical classification. Prognostic performance was evaluated using disease-free survival (DFS) across training, internal validation, and external validation sets. Deep learning classifiers identified distinct patient clusters with significantly different DFS based on TC and IM. For both IM and TC analysis, patients in the favorable group had a better DFS in all sets (IM: <i>p</i> < 0.001, <i>p</i> = 0.04, <i>p</i> = 0.02; TC: <i>p</i> = 0.002, <i>p</i> = 0.01, <i>p</i> = 0.12, respectively). Combining classifiers enhanced prognostic accuracy in all sets (<i>p</i> < 0.001, <i>p</i> = 0.01, <i>p</i> = 0.06, respectively). The model outperformed traditional clinical variables and CD3 enumeration, which demonstrated variability across cohorts. Automated deep learning analysis of CD3-stained slides enables robust and reproducible prognostic stratification in stage III colon cancer, independently of staining and scanning variations. This approach holds promise for guiding personalized treatment strategies.<b>ClinicalTrials.gov Identifiers:</b> NCT00265811, NCT00995202.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2668797"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prednisolone modulates CD8⁺ and regulatory T-cell activity to dampen response to immune checkpoint inhibitor therapy in melanoma.","authors":"Jesse R Brown, Bernadette Pedersen, Georgina V Long, Nigel G Maher, Su Yin Lim, Helen Rizos, Elena Shklovskaya","doi":"10.1080/2162402X.2026.2643494","DOIUrl":"10.1080/2162402X.2026.2643494","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, yet their efficacy is limited by high-grade immune-related adverse events that often require treatment with systemic corticosteroids. Although corticosteroids are widely used, their impact on anti-tumor immunity remains poorly defined. Using an ICI-responsive murine melanoma model, we show that tapered systemic prednisolone administered after three cycles of combined anti-CTLA4 and anti-PD1 therapy compromises ICI-mediated tumor control, leading to delayed progression in one-third of initially responding animals. Mechanistically, prednisolone selectively suppressed CD8⁺ effector T-cell activation in tumor-draining lymph nodes and in the circulation, while expanding activated regulatory T-cells. These changes increased the Treg:CD8⁺ effector ratio, reduced cytotoxic T-cell function and blocked the early ICI-mediated induction of cytokines, including IL-2, IFNγ, VEGF, CCL3/4, IL-13, IL-3, and GM-CSF. Importantly, despite these early immunosuppressive effects, long-term tumor-specific memory responses were preserved. Autologous melanoma:T-cell cocultures validated these findings. Overall, systemic prednisolone disrupts early CD8⁺ T-cell-mediated anti-tumor activity but spares durable immunity, highlighting the critical importance of timing and context in the introduction of corticosteroids during ICI therapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2643494"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12987513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FTL008.16, a 5T4-Conditional 4-1BB bispecific antibody, potently enhances antitumor immunity via tumor-directed t-cell activation.","authors":"Shuang Liu, Ziqing Ren, Yongyan Tu, Pengyu Chen, Yinglu Zhang, Shengyan Zhao, Xiaofeng Chen, Han Deng, Shuyun Yang, Feng Qu, Ming Zhang, Lantu Gou, Qing Li, Ying Huang, Fanxin Ma, Jinliang Yang","doi":"10.1080/2162402X.2026.2684136","DOIUrl":"10.1080/2162402X.2026.2684136","url":null,"abstract":"<p><p>The clinical development of 4-1BB agonists for cancer immunotherapy has been constrained by dose-limiting toxicities, particularly hepatotoxicity. To overcome this challenge, we developed FTL008.16, a novel bispecific antibody targeting 4-1BB (CD137) on T cells and the tumor-associated antigen 5T4. FTL008.16 is a human IgG1 antibody bearing an effector-deficient Fc region that specifically binds 4-1BB at an epitope overlapping with that of its natural ligand (4-1BBL), potentially mimicking physiological 4-1BBL-mediated co-stimulation. As demonstrated through <i>in vitro</i> reporter assays and primary cell-based systems, FTL008.16 elicits dose-dependent 4-1BB activation strictly contingent on 5T4 engagement, enhancing T-cell proliferation, cytokine secretion, and tumor cell lysis, thereby demonstrating potent antitumor efficacy in preclinical models. <i>In vivo</i>, FTL008.16 exhibited superior efficacy over a conventional anti-4-1BB monoclonal antibody, suppressing established tumors in both CT26 and MC38 models, with complete regression observed in CT26 tumors. In cynomolgus monkeys, FTL008.16 demonstrated an excellent safety profile, with no elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) observed even at 50 mg/kg. Importantly, this 5T4-restricted activation mechanism confines immune stimulation to the tumor microenvironment, thereby circumventing the systemic toxicity associated with conventional 4-1BB agonists. Collectively, these findings establish FTL008.16 as a conditionally active immunotherapeutic agent that successfully achieves both robust antitumor efficacy and a favorable safety profile.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2684136"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148220289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional immune profiling uncovers biphasic peripheral T-cell dynamics after chemoradiation in patients with locally advanced head and neck cancer.","authors":"Benoît Lecoester, Yaoyao Xie, Xushan Sun, Adeline Renaudin, Babacar Ndao, Laura Boullerot, Marine Malfroy, Rudy Arnier, Cyril Boisson, Caroline Laheurte, Aurelia Meurisse, Cédric Chevalier, Noémie Vulquin, David Thibouw, Salim Benhmida, Mandy Pernot, Dewi Vernerey, Céline Mirjolet, Junming Guo, Jihane Boustani, Olivier Adotevi","doi":"10.1080/2162402X.2026.2635806","DOIUrl":"10.1080/2162402X.2026.2635806","url":null,"abstract":"<p><p>Cisplatin-based concurrent chemoradiation (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Attempts to combine immune checkpoint inhibitors with CRT have not improved outcomes, underscoring the need to better understand CRT-driven immunologic dynamics. Here, we performed longitudinal, multidimensional profiling of peripheral immunity in patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after platinum-based CRT. CRT induced a transient reduction in tumor-reactive Th1 responses at CRT-1M, followed by marked expansion by CRT-3M. Consistently, genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic pattern with delayed upregulation at CRT-3M. Transcriptomic analyses of blood lymphocytes revealed an early shift from B-cell- to T-cell-mediated pathways over time during CRT. Integrated analyses including immunosuppressive cells and soluble mediators showed that the early decline in tumor-reactive T cells coincided with increased immunosuppressive cells, T-cell exhaustion, and elevated protumoral cytokines such as IL-8, IL-1β, and IL-10. In contrast, robust expansion of tumor-reactive T cells dominated the peripheral immune landscape at CRT-3M. Together, these data reveal the dynamic remodeling of peripheral immunity following platinum-based CRT and identify a delayed peripheral immune activation phase that may represent an optimal window for combining CRT with immune checkpoint blockade.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2635806"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147311595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 genetic fate mapping uncovers immune cell diversity mediating the efficacy of combined PD-1 blockade and chemotherapy.","authors":"Ayuko Yamaguchi, Haruka Suzuki, Shunsuke Takasuga, Megumi Tatematsu, Akane Fuchimukai, Tentaro Endo, Haruka Kaya, Aoi Morishita, Shinsuke Seki, Kazuhiro Imai, Takashi Ebihara","doi":"10.1080/2162402X.2026.2639723","DOIUrl":"10.1080/2162402X.2026.2639723","url":null,"abstract":"<p><p>Combined cytotoxic chemotherapy and immune checkpoint inhibition (ICI) improves outcomes in PD-L1-low lung cancer, but transient and broad PD-1 expression across immune cells complicates the understanding of the underlying mechanisms. We generated Pdcd1-CreERT2 fate-mapping mice to trace PD-1-expressing cells via tdTomato during PD-1 blockade. PD-1-fate-mapped lymphocytes downregulated PD-1 in the spleen but largely retained it in tumors, except for NK cells, which lost PD-1 and regained function. Single-cell transcriptional profiling was performed on immune cells in PD-L1-low Lewis lung carcinoma (LLC) treated with cyclophosphamide (CTX) and/or anti-PD-1 antibodies. Anti-PD-1 monotherapy showed limited efficacy, whereas CTX plus anti-PD-1 markedly improved tumor control. Single-cell analysis identified 15 transcriptionally distinct immune clusters with treatment-dependent abundances. Combination therapy expanded cytotoxic CD8 T cells and a dysfunctional Treg cluster, enhancing CTL activity, including PD-1-fate-mapped CD8 T cells expressing Tpex1 markers. Single-cell TCR analysis revealed that clonotypes selectively expanded by combination therapy, mediating potent cytotoxicity against LLC tumors. PD-1 blockade synergizes with cytotoxic chemotherapy to diversify and expand PD-1 lineage-traced CTL clonotypes, driving robust antitumor immunity. Thus, our fate-mapping system is a valuable tool to search for immune cells responsive to ICI therapy.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2639723"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147366935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}