Immunotherapy advances最新文献

{"title":"Optimized procurement of cancer-reactive T-cell receptors from clinical samples.","authors":"Marine E Caillaud, Cristina Rius, Théo Morin, Li Rong Tan, Hannah L Thomas, Amber Rogers, Joshua Hick, Morten Nielsen, Md Samiul Hasan, Inge Marie Svane, Barbara Szomolay, Andrew K Sewell, Garry Dolton","doi":"10.1093/immadv/ltag009","DOIUrl":"https://doi.org/10.1093/immadv/ltag009","url":null,"abstract":"<p><p>T-cell receptors can sense cancer-associated changes in cellular proteins, lipids, metabolites, and stress pathways, enabling immune-mediated tumour elimination in some patients. These receptors underpin T-cell receptor-based immunotherapies, yet their isolation from clinical samples remains challenging due to labour-intensive workflows, dependence on prior antigen knowledge, and loss of cell viability. We developed an optimized flow cytometry-based assay, termed the T107 assay, to isolate viable cancer-reactive T-cells directly from clinical samples. Following short-term exposure to cancer cells, responding T-cells are identified by simultaneous surface detection of tumour necrosis factor and the degranulation marker CD107a, enabling recovery of live antigen-reactive cells for downstream analysis. The T107 assay enabled rapid identification of cancer-reactive T-cells from tumour-infiltrating lymphocyte products derived from melanoma and sarcoma patients. The assay supported phenotypic and functional characterization of αβ and γδ T-cell receptor populations, including CD4⁺ and CD8⁺ subsets, responding to both patient-specific and shared cancer antigens. Isolation of viable responding cells enabled high-resolution receptor sequencing, generation of functional T-cell clones, determination of antigen specificity and major histocompatibility complex restriction or independence. Paired receptors were engineered into primary T-cells to generate T-cell receptor-engineered products capable of recognizing multiple cancer types. The T107 assay provides a rapid and robust method for antigen-agnostic procurement of viable cancer-reactive T-cells and their receptors from clinical material. This approach removes key bottlenecks in T-cell receptor discovery and is expected to accelerate development of T-cell receptor-based immunotherapies across a broad range of cancers.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag009"},"PeriodicalIF":4.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRC5 expression within tumor cells is critical to activate adaptive and innate antitumor immune responses.","authors":"Akhil Shukla, Mohammad Moradzad, Akouavi Julite Irmine Quenum, Jean-François Lucier, Anny Armas Cayarga, Dominique Lévesque, François-Michel Boisvert, Thomas A Kufer, Sheela Ramanathan, Subburaj Ilangumaran","doi":"10.1093/immadv/ltag010","DOIUrl":"10.1093/immadv/ltag010","url":null,"abstract":"<p><strong>Introduction: </strong>Tumors downregulate NLRC5 expression to reduce MHC-I and evade CD8⁺ T cell-mediated killing. Introducing full-length NLRC5 (N5FL) or NLRC5-CIITA chimeric protein (N5CA) can restore tumor immunogenicity. Here, we elucidated the underlying mechanisms and also evaluated the requirement of NLRC5 expression in antigen-presenting cells (APCs) of the host for tumor control.</p><p><strong>Materials and methods: </strong><i>Nlrc5^-/-</i> and <i>Nlrc5^+/+</i> mice were implanted with B16-F10 melanoma expressing N5FL or NC5A. Tumor growth, activation of lymphoid cells, their infiltration into tumors and the requirement for tumor control were assessed. The proteomes of B16-F10 cells expressing N5FL or N5CA were analyzed.</p><p><strong>Results: </strong>NLRC5-expressing tumors were efficiently controlled in both <i>Nlrc5^+/+</i> and <i>Nlrc5^-/-</i> mice, characterized by infiltration of CD8⁺ and CD4⁺ cells, natural killer (NK) cells, NK T (NKT) cells and invariant NKT (iNKT) cells, increased tumor vascularization and upregulation of <i>Ccl4</i> and <i>Cxcl9</i> genes. Both CD8⁺ and NK1.1⁺ cells contribute to NLRC5-dependent tumor control. NLRC5 expression in the Tumor Cancer Genome Atlas-skin cutaneous melanoma correlated with NK cell markers and nonclassical MHC-Ib expression. Proteomes of NLRC5-expressing tumor cells showed downmodulation of dominant tumor antigens, but displayed significant changes in the lysosome and the proteasome pathways, upregulated the protein processing in endoplasmic reticulum pathway, and downregulated the autophagy pathway, all of which could impact processing and presentation of subdominant tumor antigens.</p><p><strong>Conclusion: </strong>NLRC5 expression in APCs is dispensable for NLRC5-dependent antitumor immunity. NLRC5-dependent tumor control requires both CD8⁺ and NK1.1⁺ cells. Tumor-intrinsic NLRC5 promotes vasculature that is permissive to infiltration by antitumor immune cells. In addition to upregulating MHC-I, NLRC5 may enhance alternative antigen-processing pathways and attenuate autophagic degradation of MHC-I, thereby augmenting tumor immunogenicity.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag010"},"PeriodicalIF":4.4,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular adenosine released by mesenchymal stromal cells from young hosts boosts the antimicrobial activity of neutrophils from aged hosts against <i>Streptococcus pneumoniae</i>.","authors":"Rania Hassan Mohamed, Michael C Battaglia, Elsa N Bou Ghanem","doi":"10.1093/immadv/ltag007","DOIUrl":"10.1093/immadv/ltag007","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSC) represent a potential target to reverse inflammaging and to halt immunosenescence, as these cells can modulate immune cell responses. Neutrophils, known as polymorphonuclear leukocytes (PMNs), are required for host defence against bacterial pathogens such as <i>Streptococcus pneumoniae</i>; however, their function significantly declines with age. Whether MSCs can reverse the age-driven decline in PMN antibacterial function is unknown. To test that, we cultured MSCs from young and aged mice and tested the paracrine effect of factors present in the conditioned media (CM) on antimicrobial responses of PMNs across host age. The <i>ex vivo</i> treatment with MSCs-CM from aged mice blunted the antimicrobial activity of PMNs from young hosts. However, treatment of PMNs from aged mice with young MSCs-CM significantly increased <i>S. pneumoniae</i> uptake, production of mitochondrial reactive oxygen species, and boosted overall bacterial killing. In exploring the pathways involved, we found that presence of immune modulatory extracellular adenosine in the young MSCs-CM was required for boosting PMN responses. Further, in contrast to aged mice MSCs-CM, young mice MSCs CM increased the responsiveness of aged mice PMNs to adenosine activation by upregulating the A1 adenosine receptor expression. Blocking this high affinity adenosine receptor reversed the rejuvenating effect of young mice MSCs-CM on bacterial killing by PMNs from aged hosts. In summary, this study suggests a potential cell-free therapeutic role of the young host MSC secretome in reversing the age-driven defects in PMN function against bacterial infection. It is the first study to demonstrate an anti-immunosenescence activity of the MSC secretome through extracellular adenosine.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag007"},"PeriodicalIF":4.4,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The resilient subset: cancer stem cells at the core of immunotherapy resistance.","authors":"Julián A Gajón, Diego Esperante, Nahuel Ko, Aaron Jimenez-Miranda, Samira Muñoz-Cruz, Ezequiel Fuentes-Panana, Laura C Bonifaz","doi":"10.1093/immadv/ltag006","DOIUrl":"10.1093/immadv/ltag006","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are a small subset of cells that possess unique characteristics, including the ability to initiate and sustain tumor growth, self-renew, and differentiate into various types of cancer cells. They play a crucial role in tumor progression, metastasis, and recurrence. In recent years, CSCs have garnered significant attention due to their involvement in therapeutic resistance to both conventional and novel cancer treatments, including immunotherapy. This review delves into the fundamental properties of CSCs, molecular, cellular, and metabolic, focusing particularly on their immunomodulatory effects. We propose a comprehensive model that reflects the involvement of CSCs in various interlinked contexts, including key signaling pathways, the suppressive microenvironment, and the surrounding stromal components. Through this triaxial conceptualization, we highlight the key role of the stemness-orchestrated architecture in contributing to therapeutic failure. We present evidence gathered from diverse clinical settings, demonstrating a tight correlation between a stem tumor phenotype and poor clinical outcomes, including reduced survival rates and dampened response to immune checkpoint inhibitors (ICB). Finally, we propose therapeutic interventions specifically designed to disrupt the architecture of cancer stemness. These include vaccination against CSC antigens, differentiation therapies, cellular therapies, and combinatorial approaches. In summary, this review apprises an integral, up-to-date perspective that redefines the role of CSCs, positioning them at the core of immunotherapeutic resistance.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag006"},"PeriodicalIF":4.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of hyaluronidase-facilitated subcutaneous immunoglobulin 10% in pediatric patients with primary immunodeficiency disease.","authors":"Zhaoyang Li, Yang Teng, Sharon Russo-Schwarzbaum, Barbara McCoy","doi":"10.1093/immadv/ltag003","DOIUrl":"10.1093/immadv/ltag003","url":null,"abstract":"<p><strong>Introduction: </strong>Hyaluronidase-facilitated subcutaneous immunoglobulin 10% (fSCIG 10%) is a unique and effective treatment for primary immunodeficiency disease (PID), allowing for less frequent administration than conventional subcutaneous immunoglobulin therapies.</p><p><strong>Methods: </strong>The pharmacokinetics (PK) of fSCIG 10% in pediatric patients (aged 2 to <16 years at screening) with PID was assessed in a prospective, phase 3, open-label, multicenter, clinical trial conducted in the USA. Patients previously treated with intravenous or conventional subcutaneous immunoglobulin therapy (consistent dose for ≥3 months) received fSCIG 10% via a dose ramp-up schedule for ≤6 weeks (Epoch 1), then at full target dose every 3-4 weeks for ≤3 years (Epoch 2). Serum total immunoglobulin G (IgG) trough levels were reported throughout Epoch 2 across pediatric age groups (2 to <6, 6 to <12, and 12 to ≤16 years); serial PK were characterized at the Month 6 infusion. In total, 44 patients (mean age: 9.0 years; 59% male and 91% White) were eligible for the study.</p><p><strong>Results: </strong>Mean total IgG trough levels during Epoch 2 were similar across age groups. Geometric mean area under the IgG concentration-time curve per week ranged from 63.4 to 76.8 g·day/L, and body weight-adjusted apparent clearance ranged from 1.5 to 1.9 ml/day/kg.</p><p><strong>Conclusion: </strong>This study showed that serum total IgG trough levels were effectively maintained in pediatric patients with PID treated with fSCIG 10%, regardless of age. The dosing strategy for pediatric patients should be informed by assessing individual IgG levels and clinical status as for adults.</p><p><strong>Clinical trials registration: </strong>The study is registered with the ClinicalTrials.gov registry at https://clinicaltrials.gov/ct2/study/NCT03277313 (ClinicalTrials.gov Identifier: NCT03277313).</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag003"},"PeriodicalIF":4.4,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13049483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chimeric CD3ζ chains containing CD28 signalling motifs enhance antigen-specific IL-2 production and expansion of human TCR-engineered T cells <i>in vitro</i>.","authors":"Samuel J Burgess, Hans J Stauss, Emma C Morris","doi":"10.1093/immadv/ltaf038","DOIUrl":"10.1093/immadv/ltaf038","url":null,"abstract":"<p><p>Gene-engineered T-cell products have been developed for immunotherapy to treat cancers, with great success observed in haematological malignancies but limited efficacy in treating solid cancers. TCR-engineered T cells utilize transferred TCRs targeting tumour-associated and cancer-specific peptides presented by MHC molecules. The CD3ζ chains are part of the TCR-CD3 complex expressed by T cells and mediate signal transduction when the TCR binds to MHC-presented peptides. In this study, we explored whether co-stimulation domains, that were effective in improving the function of T cells engineered with chimeric antigen receptors (CARs), can be exploited to improve the functionality of TCR-engineered T cells. We inserted the signalling domains of CD28 or 4-1BB at the membrane proximal or the membrane distal position of the intracellular tail of CD3ζ and engineered human T cells to express a specific TCR in combination with either modified CD3ζ or unmodified control. Antigen-specific <i>in vitro</i> stimulation assays revealed that T cells expressing CD3ζ constructs with CD28 signal domains displayed enhanced peptide-specific IL-2 production and, following repeated antigen stimulation, expanded to substantially greater numbers than T cells expressing unmodified CD3ζ. Importantly, greater expansion seen with the CD28-containing ζ did not result in any reduction of effector function as assessed by peptide-specific cytotoxicity and cytokine production. The data indicate that modification of the CD3ζ chain with a CD28 signal motif provides an opportunity to improve antigen-specific expansion and effector function of TCR-engineered T cells by combining signal 1 and co-stimulatory signal 2 in one molecular TCR-CD3 complex.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf038"},"PeriodicalIF":4.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13042253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overall survival by baseline and on-treatment systemic immune-inflammation index in patients with advanced cancer receiving immune checkpoint inhibitors: a large single-centre cohort study.","authors":"Oliver John Kennedy, Rebecca Lee, Fiona Blackhall, Ananya Choudhury, Robert Metcalf, Tom Waddell, Paul Lorigan","doi":"10.1093/immadv/ltaf031","DOIUrl":"10.1093/immadv/ltaf031","url":null,"abstract":"<p><p>The Systemic Immune-Inflammation Index (SIII; neutrophils/lymphocytes × platelets) is a low-cost biomarker proposed to predict outcomes with immune checkpoint inhibitors (ICIs). This study evaluated associations of baseline and early on-treatment changes in SIII with overall survival (OS) for common ICI regimens. Patients with advanced cancer treated with ICIs at a UK centre were categorized by baseline SIII (above vs. below the median) and by changes at 3-6 weeks (increase/decrease). OS was analysed using Kaplan-Meier estimates. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable Cox regression. Among 2578 patients included, 1514 deaths occurred over a median follow-up of 2.6 years. Common regimens included pembrolizumab or atezolizumab with (15.9%) or without chemotherapy (13.9%) for NSCLC, and nivolumab plus ipilimumab for melanoma (12.6%). Lower baseline SIII was associated with improved OS (28.1 vs. 11.1 months; aHR 0.56, 0.50-0.62), with a weaker association observed in those receiving ICI-targeted therapy combinations. An on-treatment increase in SIII was linked to reduced OS (16.8 vs. 21.5 months; aHR 1.33, 1.18-1.49). Patients with low baseline SIII and an on-treatment decline had the longest OS (33.2 months), whereas those with high baseline SIII and an on-treatment increase had the shortest (8.2 months; aHR 2.88, 2.41-3.44; interaction between baseline and on-treatment SIII <i>P</i> < 0.001). SIII is a low-cost, readily available biomarker. Both baseline SIII levels and on-treatment changes in SIII are significantly associated with OS. SIII may help identify patients who could benefit from closer monitoring or treatment adjustments.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf031"},"PeriodicalIF":4.4,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13023032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 inhibitor-induced rheumatic, endocrine, and sarcoidosis-like immune-related adverse events in metastatic melanoma are associated with improved survival and lower corticosteroid exposure.","authors":"Maria Lindén, Hifaa Al Remawi, Anna Fager, Levent M Akyürek, Anna Rudin, Lars Ny, Sara Bjursten, Ankur Pandita, Max Levin","doi":"10.1093/immadv/ltag004","DOIUrl":"10.1093/immadv/ltag004","url":null,"abstract":"<p><strong>Introduction: </strong>Programmed cell death protein 1 (PD-1) inhibitors improve survival in advanced melanoma but can induce immune-related adverse events (irAEs). IrAEs have been linked to better outcomes. However, it remains unclear whether specific irAE types drive this effect and how corticosteroid treatment of irAEs influences survival.</p><p><strong>Materials and methods: </strong>A seven-year retrospective cohort study of 301 patients with advanced cutaneous melanoma treated with single-agent PD-1 inhibition at Sahlgrenska University Hospital. irAEs were identified using CTCAE v4.0/v5.0, and irAEs requiring systemic corticosteroids or endocrine replacement therapy were included. Corticosteroid therapy was categorized as low dose (≤0.5 mg/kg prednisolone equivalent) or high dose (>0.5 mg/kg). Overall survival (OS) was assessed using Kaplan-Meier and Cox models, including time-dependent analyses to address immortal time bias.</p><p><strong>Results: </strong>Patients with irAE (109 of 301 patients) had longer OS than those without irAEs. Of the eight most common irAEs, four were associated with superior survival, one was borderline significant, and three were non-significant. Rheumatic irAEs and late-onset thyroid irAEs remained associated with improved OS after adjustment for negative prognostic factors and immoral time bias. Colitis irAE were borderline significant in univariate analysis. Sarcoidosis-like and hypophysitis irAEs were rare but conferred excellent outcomes. Hepatitis, nephritis, and pneumonitis were not associated with better survival. Most survival-associated irAEs were treated with a lower start dose of corticosteroids but duration and time to onset were similar to non-survival-associated irAEs.</p><p><strong>Conclusion: </strong>Rheumatic, endocrine, and sarcoidosis-like irAEs are markers of superior survival and suggest that lower initial corticosteroid doses may preserve PD-1 inhibitor efficacy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag004"},"PeriodicalIF":4.4,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuraminidase A controls pneumococcal recognition and fate: deficiency enhances immune sensing and intracellular survival, while treatment promotes phagocytic clearance.","authors":"Kristine Farmen, Georgia Yfanti, Fabienne Geers, Johanna Hollenbeck, Miguel Tofiño Vian, Thomas P Kohler, Sven Hammerschmidt, Federico Iovino","doi":"10.1093/immadv/ltag002","DOIUrl":"10.1093/immadv/ltag002","url":null,"abstract":"<p><p><i>Streptococcus pneumoniae</i> (pneumococcus) is a leading cause of bacterial meningitis worldwide and is associated with cerebrovascular complications and long-term neurological sequelae. These outcomes are largely driven by an excessive yet ineffective neuroinflammatory response. Although pneumococci express multiple virulence factors that enable immune evasion, how these factors modulate phagocytic responses in the central nervous system remains unclear. Here, we identify neuraminidase A (NanA) as a critical regulator of phagocytic activation in microglia and macrophages. Using murine and human microglia and RAW 264.7 macrophages, we show that NanA deficiency increases bacterial adhesion, indicating enhanced immune recognition, but paradoxically promotes intracellular bacterial survival. Despite elevated expression of the phagocytic marker CD68, microglia infected with NanA-deficient pneumococci fail to efficiently eliminate intracellular bacteria, as evidenced by unchanged levels of the lysosomal enzyme cathepsin 3 compared with NanA-expressing strains. Treatment with recombinant NanA restored phagocytic activation and significantly enhanced clearance of NanA-deficient bacteria. This effect was dependent on NanA sialidase activity, as enzymatically inactive NanA failed to restore immune sensing. Notably, this immunomodulatory function was specific to the secreted form of NanA produced by the invasive TIGR4 strain and was not observed with membrane-anchored NanA from D39-derived mutants. Together, these findings reveal an unexpected role for NanA in promoting effective innate immune activation and bacterial clearance, highlighting its potential as a therapeutic target for pneumococcal meningitis and invasive pneumococcal disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag002"},"PeriodicalIF":4.4,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13001807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147500857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive spatial and immune profiling of metastatic mismatch repair-deficient colorectal cancer reveals response to immunotherapy.","authors":"Ilkyu Park, Hari Kang, Se-Hee Kim, YunJae Jung, Won-Suk Lee","doi":"10.1093/immadv/ltag001","DOIUrl":"10.1093/immadv/ltag001","url":null,"abstract":"<p><strong>Introduction: </strong>Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit variable clinical responses to immune checkpoint inhibitors (ICIs) despite their high immunogenicity.</p><p><strong>Methods: </strong>To investigate the molecular and spatial determinants of this heterogeneity, we analyzed five metastatic sites (colon, liver, peritoneum, left ovary, and right ovary) from a dMMR CRC patient treated with pembrolizumab using bulk and single-cell RNA sequencing combined with multiplex immunohistochemistry.</p><p><strong>Results: </strong>Responsive lesions were characterized by enriched cytotoxic and interferon-γ signatures, greater CD8⁺ T-cell infiltration, and close spatial proximity between programmed death-ligand 1(PD-L1)⁺ tumor cells and M1-like macrophages. In contrast, resistant lesions demonstrated reduced effector cell presence and were enriched in immunosuppressive programs, including SPP1⁺ and CD163⁺ macrophages, noncanonical WNT5A/B signaling, and TGF-β-mediated matrix remodeling.</p><p><strong>Conclusion: </strong>Collectively, these findings highlight the importance of spatial immune architecture and macrophage polarization in shaping ICI responses in dMMR CRC and underscore the need for spatial profiling to guide immunotherapy strategies in metastatic disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag001"},"PeriodicalIF":4.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12898929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146203547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}