Frontiers in Immunology最新文献

Background: Non-small cell lung cancer (NSCLC) with brain metastasis (BM) is associated with poor prognosis. For those patients with MET exon 14 skipping mutation (METex14), although MET tyrosine kinase inhibitors (MET TKIs) have emerged, but their efficacy remains limited, with the median progression-free survival (PFS) no more than 14 months. Herein, we present a case of a NSCLC patient with BM and METex14, who achieved prolonged PFS of 41 months following brain radiotherapy initiation and camrelizumab (a PD-1 inhibitor).

Case presentation: A 75-year-old man was diagnosed with lung adenocarcinoma with BM and METex14. He received 7 months of crizotinib as first-line therapy, after that, the lung and brain lesions enlarged. Then, programmed cell death-ligand 1 (PD-L1) showed the tumor proportion score (TPS) approximately 80%, he underwent brain radiotherapy combined with camrelizumab immunotherapy. After treatment, the lesions in the patient's lung and brain were significantly reduced. Camrelizumab maintenance therapy was continued for 20 months until the appearance of pulmonary aspergillosis, with the patient achieving a PFS of 41 months.

Conclusion: The combination of brain radiotherapy and camrelizumab demonstrated efficacy in a lung adenocarcinoma patient with BM and METex14. These findings suggest that immunotherapy may represent a potential treatment approach for high PD-L1 expression of METex14 NSCLC patients, warranting further investigation in larger cohorts.

The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Among the central regulators of immune suppression, CD38, a multifunctional ectoenzyme and surface glycoprotein, has emerged as a pivotal orchestrator. CD38 is abundantly expressed on regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), where it enhances survival, metabolic fitness, and suppressive activity. Invariant natural killer T (iNKT) cells, which can either promote or suppress antitumor immunity, also express CD38 upon activation, suggesting a role for CD38 in directing their context-dependent fate within the TME. Mechanistically, CD38 regulates immune suppression through NAD⁺ hydrolysis, calcium signaling, and promotion of fatty acid oxidation (FAO) while impairing effector T-cell glycolysis and mitochondrial fitness under chronic hypoxia-conditions that favor exhaustion rather than enhanced cytotoxicity. By depleting extracellular NAD⁺, CD38 diminishes glycolysis and mitochondrial oxidative phosphorylation in effector T cells, while sustaining regulatory cell persistence through FAO. Its enzymatic products, cyclic ADP-ribose (cADPR) and NAADP, further mobilize calcium fluxes that reinforce suppressive function. CD38 also integrates with hypoxia-driven pathways; in CD38⁺ Bregs, stabilization of HIF-1α and induction of FAO-related genes such as CPT1A and PPARα/γ promote angiogenesis, immune-evasion, and therapeutic resistance. Therapeutically, targeting CD38 with monoclonal-antibodies, small-molecule inhibitors, or combinations with checkpoint blockade and macrophage-reprogramming agents has shown promise. Such interventions reverse immune suppression, restore effector T cell activity, and enhance tumor responsiveness to immunotherapy. In summary, CD38 functions as both a metabolic regulator and an immunologic checkpoint, coordinating suppressive networks and shaping iNKT cell fate. These multifaceted roles position CD38 as a transformative target for next-generation immunotherapies.

Background: Vascularized composite allotransplantation (VCA) offers unique reconstructive solutions for severe tissue loss, restoring form and function. Acute and chronic rejection remains a significant barrier, with acute episodes occurring in most recipients and chronic rejection persisting as the leading cause of graft failure. Unlike solid organ transplantation, VCA involves highly immunogenic tissues, like skin and mucosa, making rejection more frequent and challenging to manage.

Methods: A systematic review was conducted following PRISMA 2020, searching PubMed/MEDLINE, EMBASE, and Web of Science for original human VCA studies reporting immunosuppressive protocols and outcomes in acute or chronic rejection. Quality was assessed using the Newcastle-Ottawa Scale and Level of Evidence; extracted data included demographics, regimens, rejection episodes, treatments, and graft survival.

Results: Fourty-six studies (136 recipients) met inclusion criteria: upper extremity (n=69; 51%), face (n=33; 24%), abdominal wall (n=33; 24%), scalp and penile (each n=1; 0.7%). Acute rejection occurred in 81/136 (60%) within year 1, most often at POW 1-2 (n=52), 5-12 (n=42), and 13-52 (n=30). Severity was Banff grade I (n=49; 36%), II (n=73; 54%), III (n=50; 37%), and severe IV (n=1; 0.7%). Common symptoms included skin lesions (n=43; 32%), edema (n=32; 24%), erythema (n=29; 21%), and rash (n=15; 11%), with some experiencing numbness (n=4; 2.9%), tingling (n=5; 3.7%), or burning sensations (n=5; 3.7%). Corticosteroids were the mainstay (n=98; 72%)-methylprednisolone (n=31; 23%), clobetasol (n=15; 11%), and prednisone (n=11; 8.1%); tacrolimus was used in 49 (36%), including topical in 29 (21%). Other immunosuppressants included antithymocyte globulin (n=19; 14%), alemtuzumab (n=11; 8.1%), mycophenolate mofetil (n=11; 8.1%), and rituximab (n=6; 4.4%); basiliximab (n=4; 2.9%), sirolimus (n=2; 1.5%), and plasmapheresis (n=4; 2.9%) were used selectively. Monotherapy was used in 42 episodes, and dual therapy in 51, most commonly methylprednisolone plus topical tacrolimus (n=26).

Conclusion: This review underscores the ongoing challenge of rejection in VCA and the need for improved treatment strategies, with corticosteroids, calcineurin inhibitors, and mycophenolate mofetil remaining standard while emerging biologicals offer promise. Acute rejection is often manageable yet threatens graft survival, whereas chronic rejection is less reported, likely under-recognized and harder to treat, underscoring need for novel immunomodulators, standardized protocols, and prevention to improve outcomes.

Background: Penile cancer (PeCa) is a rare but aggressive disease where lymph node metastases (LNM) represent the most significant prognostic factor. Accurate identification of LNM remains a clinical priority, but traditional imaging and clinical parameters often fail to detect occult LNM. Soluble immune checkpoint proteins (sICs) have recently emerged as potential non-invasive biomarkers in various malignancies, although unexplored in PeCa. The primary aim of this study was to explore the value of a panel of 14 sICs for predicting LNM in PeCa. The secondary aim was to compare plasma sIC levels between PeCa patients and cancer-free controls.

Methods: Using ProcartaPlex immunoassays, BTLA, IDO, LAG-3, HVEM, PD-1, PD-L1, PD-L2, TIM-3, CD80, CTLA-4, GITR, CD27, CD28, and CD137 were measured in plasma from 284 PeCa patients and 45 cancer-free controls. PeCa patients were divided into a training set (n=202) and a test set (n=82). A prediction model for LNM was created using logistic regression.

Results: Overall accuracy of the prediction model reached 77.5% (95% CI: 70.9 - 83.3) for the training set, yielding 8.9% sensitivity and 99.3% specificity in predicting LNM. Upon validation using the test set, the accuracy decreased to 62.2% (95% CI: 50.8-72.7) with 17.9% sensitivity and 85.2% specificity. When comparing PeCa patients and cancer-free controls, four inhibitory sICs (IDO, TIM-3, CD80, and CTLA-4) were found at significantly higher levels in the PeCa group. Due to the rarity of the disease, the main limitation of the study is the small number of patients with LNM.

Conclusion: Our study provides no evidence that sICs can predict LNM in PeCa, although four inhibitory sICs were significantly elevated in PeCa patients compared to cancer-free controls, suggesting systemic immunosuppression associated with tumor presence, consistent with findings in other malignancies. Studies with larger cohorts are warranted to clarify the prognostic significance of sICs in PeCa.

Introduction: Equine herpesvirus type 1 (EHV-1) is a major veterinary pathogen causing significant economic losses in the livestock industry. Despite its impact, effective vaccines and targeted antiviral strategies remain limited, largely due to an incomplete understanding of host factors regulating viral replication and pathogenesis.

Methods: To systematically identify host genes essential for EHV-1 infection, we established a BHK-21 cell line stably expressing Cas9 and performed a genome-wide CRISPR/Cas9 knockout screen using a pooled lentiviral single-guide RNA library. Significantly enriched candidate genes from positive selection were validated by generating knockout cell lines. Viral replication and protein expression were assessed using quantitative polymerase chain reaction and Western blot analysis. Pathway enrichment and protein interaction network analyses were subsequently conducted.

Results: Genome-wide CRISPR/Cas9 screening identified multiple host factors critical for EHV-1 replication. Pathway enrichment analysis revealed that these genes were involved in key cellular signaling and regulatory networks associated with viral infection. Functional validation demonstrated that knockout of selected host genes significantly suppressed EHV-1 replication and viral protein synthesis.

Discussion: These findings highlight essential host determinants required for EHV-1 replication and suggest that targeting host factors may represent a promising strategy for antiviral intervention. This study provides a foundation for the development of host-directed immunotherapeutic and antiviral approaches against EHV-1 infection.

Background: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) frequently develop rapidly progressive interstitial lung disease and may also exhibit hepatic dysfunction, yet the mechanisms of hepatic injury remain poorly defined. We investigated the roles of M2-like macrophages and complement activation in hepatic injury associated with anti-MDA5 antibody-positive DM.

Methods: Liver specimens from five autopsy cases of anti-MDA5 antibody-positive DM were examined for the presence of CD80-positive M1-like and CD206-positive M2-like macrophages. To establish a model of antibody-mediated hepatic injury, human MDA5 transgenic mice were treated with in-house anti-human MDA5 monoclonal antibodies. The contribution of complement was assessed by comparing hepatic pathology between wild-type and complement component C3-deficient MDA5 transgenic mice. Liver tissues were analyzed by immunohistochemistry and western blotting, and single-cell RNA sequencing libraries were generated from snap-frozen mouse liver samples.

Results: Autopsy liver specimens demonstrated the presence of CD80-positive M1-like and CD206-positive M2-like macrophages. In human MDA5 transgenic mice, administration of anti-human MDA5 monoclonal antibodies induced hepatic injury accompanied by increased infiltration of CD206-positive M2-like macrophages. This hepatic injury was markedly attenuated in C3-deficient MDA5 transgenic mice, supporting an important role for complement activation in this model.

Conclusion: Complement activation and the accumulation of M2-like macrophages are associated with anti-human MDA5 monoclonal antibody-induced hepatic injury in mice. These findings provide mechanistic insight into antibody-complement-macrophage interactions and suggest that modulation of complement pathways may represent a potential therapeutic approach to limit liver and systemic involvement in this disorder.

Introduction: Neurological complications are increasingly recognized as a significant consequence of COVID-19; however, time-resolved, brain-specific characterization of transcriptional alterations underlying SARS-CoV-2-associated neuroinflammation and neuronal injury remain limited. We hypothesized that brain transcriptional responses evolve dynamically during acute SARS-CoV-2 infection, resulting in temporal transcriptional programs.

Methods: KRT18-hACE2 transgenic mice were intranasally inoculated with SARS-CoV-2. Brain was harvested at 4 and 6 days post-infection (dpi) for analyses.

Results: Immunohistochemical analyses confirmed a broad spectrum of viral neurotropism and gliotropism, accompanied by an increased apoptotic burden, particularly in cortical neurons (ClCas3/SATB2+). Robust activation of myeloid cells (Iba1+/CD68+) provided evidence of neuroinflammation. Cytokine/chemokine profiling demonstrated pronounced upregulation of inflammatory mediators (CXCL10, IL-12p40, CCL12), alongside reduced CX3CL1, suggesting impaired neuron-microglia communication. Whole-transcriptome and gene ontology analyses uncovered stage-dependent molecular programs, with early alterations at 4 dpi enriched in protein ubiquitination, vesicle trafficking, and synaptic processes, followed by intensified innate immune activation and engagement of chromosomal maintenance pathways at 6 dpi. In parallel, pronounced suppression of mitochondrial function at 6 dpi, pointing to energy exhaustion and transcriptional-translational discordance, as supported by digital PCR and a substantial reduction in COXIV protein levels.

Discussion: These findings provide a time-resolved molecular landscape of SARS-CoV-2-induced neuroinflammation and metabolic stress, highlighting CNS vulnerability during severe infection and suggesting pathways potentially relevant to COVID-19-associated sequelae.

Introduction: Immune reconstitution is a critical parameter in successful hematopoietic cell transplantation (HCT) and involves different cell types and a microenvironment including cytokines. Natural killer (NK) cells and γδ T cells are known to repopulate early after HCT and are proposed to have the intriguing capacity of mediating graft-versus-leukemia (GVL) effects without accompanying graft-versus-host-disease (GVHD). Interleukin-15 (IL-15) and interleukin-7 (IL-7) are key homeostatic cytokines, with effects on both T and NK cells, making these cytokines especially interesting in an HCT setting.

Methods: In this prospective study, we investigated associations between IL-15 and IL-7, NK cells and γδ T cells, including activated subtypes, and clinical outcomes. We included 105 patients undergoing allogeneic HCT at a single-center institution. IL-15, IL-7, and extended T and NK cell phenotyping were measured longitudinally at fixed time points following HCT.

Results: We found high IL-15 concentrations early post-transplant to be significantly associated with reduced overall survival, reduced relapse-free survival, and excess acute GVHD. Furthermore, IL-15 showed significant inverse correlations with NK cells and γδ T cells, including activated subtypes early after HCT, and with conventional T cells at later time points. IL-7 was significantly inversely correlated not only with conventional T cells but also with γδ T cells early after HCT.

Discussion: These findings may suggest that early immune reconstitution of NK cells and γδ T cells is influenced by the bioavailability of IL-15 after HCT and that IL-15 could have a mechanistic effect in the activity of these innate effector cells. NK cells and γδ T cells are currently being investigated in several promising treatment settings, and IL-15 here may offer a potential benefit.

Objective: This study aimed to elucidate the mechanistic role of M2 tumor-associated macrophages in esophageal cancer (EC) progression and to construct an M2 macrophage-related gene signature for prognostic prediction.

Methods: Integrated analyses of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data of EC were performed. scRNA-seq data were processed with Seurat and annotated using SingleR. Immune infiltration was evaluated through ssGSEA and CIBERSORT. Weighted gene coexpression network analysis (WGCNA) was used to identify M2 macrophage-associated modules, and candidate genes were intersected with differentially expressed genes (DEGs). Functional enrichment analyses were performed, and a prognostic risk model was established through multivariate Cox regression analysis. The functional roles of key genes were validated through in vitro and in vivo experiments.

Results: Twelve cell types were identified by scRNA-seq, with macrophages representing the predominant immune population. M2 macrophages formed the major immunosuppressive subtype and were negatively associated with patient survival. WGCNA and DEG analysis identified 25 M2-related genes, from which a four-gene prognostic signature (SPINK5, A2ML1, IL1RN, IL36G) was constructed. The model effectively stratified EC patients into distinct risk groups with significantly different survival outcomes. Further in vitro experiments demonstrated that silencing IL1RN and IL36G in macrophages markedly suppressed the malignant phenotypes of esophageal cancer cells. Complementary in vivo experiments provided additional evidence, further indicating that IL1RN and IL36G play important functional roles in overall tumor progression.

Conclusion: A four-gene M2 macrophage-related prognostic model provides reliable prediction of clinical outcomes in EC. Among these genes, IL1RN and IL36G function as key regulators whose silencing inhibits M2 polarization and attenuates tumor proliferation, invasion, migration, and epithelial-mesenchymal transition.