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Results for “CD8-Positive T-Lymphocytes”

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PubMed2021

Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling.

Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.

Animals↗

PubMed2026

Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.

Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.

Humans↗

PubMed2026

Immune profiling in a living human recipient of a gene-edited pig kidney.

Xenotransplantation of gene-edited pig kidneys offers a promising solution to the shortage of kidneys for organ transplantation. We recently performed a gene-edited pig kidney transplantation into a living human recipient with end-stage kidney disease. Here, using transcriptomics, proteomics, metabolomics and multiplexed imaging, we conducted high-dimensional immune profiling in this individual. Despite profound depletion of circulating T cells, early T cell-mediated rejection occurred within 1 week after transplantation, likely driven by subtherapeutic immunosuppression and the presence of residual CD8+ T cells in lymph nodes. This T cell-mediated rejection event was reversed by intensified immunosuppression. After treatment, adaptive immunity remained suppressed, whereas innate immune activation, characterized by sustained monocyte and macrophage activity along with elevated levels of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor, persisted. Comparative transcriptomic analysis showed that xenograft rejection profiles resembled those typically observed in human allograft rejection, while also revealing unique innate immune signatures. We did not detect antibody-mediated rejection. The levels of circulating pig donor-derived cell-free DNA rose during the initial rejection episode and declined with treatment, supporting the potential of cell-free DNA measurements as a noninvasive biomarker of xenograft rejection. These findings define the distinct immune landscape of kidney xenotransplantation and highlight the need for regimens targeting both innate and adaptive immunity to improve outcomes.

Animals↗

PubMed2025

Progressive T cell exhaustion and predominance of aging tissue associated macrophages with advancing disease stage in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited understanding of the tumor immune microenvironment (TIME). The interplay between PSCC and the immune system across disease progression and HPV infection status remains poorly characterized. This study aims to assess the TIME changes from localized to advanced disease and between HPV-positive versus negative tumors to identify potential immune evasion mechanisms in advanced PSCC. scRNA-seq was performed on ten PSCC tissue samples from penile, lymph node and distant metastatic sites with four matched penile and lymph node samples to understand the cellular heterogeneity within PSCC tumors. Analysis of immune cell populations and transcriptional hallmarks were performed stratified by localized (pT1-3, N0) versus advanced (N1-3, M0 or any N, M1) disease states and HPV infection status. We observed significant differences in immune cell infiltration between localized and advanced PSCC disease states and by HPV status. Advanced disease states demonstrated an exhausted immune phenotype, characterized by terminally exhausted CD8+ T cells, M2-like macrophages and hypoxic signature, while localized disease states demonstrated an active innate immune system characterized by increased DCs. HPV-negative tumors displayed low immune cell infiltration while HPV-positive tumors demonstrated an immune exhausted phenotype. These findings offer valuable insights into the evolving PSCC immune landscape, paving the way for the development of potential therapeutic approaches for advanced PSCC.

Humans↗

PubMed2025

Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.

Tumor Microenvironment↗

PubMed2026

Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.

Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.

Animals↗

PubMed2026

In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.

T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Animals↗

PubMed2026

SLA2 is Associated With Immune evasion and Exhaustion of CD8+ T Cells in Gastric Cancer.

The Src-like adaptor 2 (SLA2) functions as a negative regulator of T cell receptor signalling. However, its involvement in the tumour microenvironment (TME) of gastric cancer (GC) remains unexplored. In this study, we found that SLA2 expression was significantly elevated in GC tissues, and a high level of SLA2 was associated with poor prognosis in GC patients. Bioinformatics analyses revealed a close association between SLA2 and TME in GC. Single-cell RNA sequencing analysis indicated that SLA2 was significantly enriched in CD8+ T cells in GC tissues. Functional validation demonstrated that SLA2 overexpression contributed to the exhaustion of CD8+ T cells by suppressing their proliferation, upregulating the expression of exhaustion markers, reducing the secretion of effector cytokines (IFN-γ and TNF-α) and impairing cytotoxic function. SLA2 knockdown in in vitro-generated exhausted CD8 T cells significantly alleviated T cell exhaustion. Mechanistically, we found that inverse promoter methylation and active histone marks (H3K27ac, H3K4me3 and H3K4me1) may regulate SLA2 expression. Our findings suggest that SLA2 may modulate the TME and promote immune evasion via CD8+ T cell exhaustion in GC.

Humans↗

PubMed2026

IgA is necessary and sufficient to prevent norovirus infection in mice.

Human norovirus is the leading cause of viral gastroenteritis, yet effective vaccines and therapeutics remain elusive. Using murine norovirus as a model, we found that mucosal immunoglobulin A (IgA) is both necessary and sufficient for protection against infection, whereas CD8+ T cells are dispensable. Robust intestinal IgA production requires at least 4 weeks of enteric infection, consistent with kinetics of human norovirus RNA clearance. Systemic vaccination elicits high titers of neutralizing serum IgG but fails to prevent enteric norovirus infection, phenocopying a recent human norovirus vaccine failure. In contrast, prophylactic delivery of dimeric anti-norovirus IgA via mRNA lipid nanoparticles confers sterilizing immunity. Together, these findings define a critical role for mucosal IgA in norovirus protection and identify IgA-based treatments as a therapeutic approach for human norovirus.

Animals↗

PubMed2016

Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype.

UNLABELLED: Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+)T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35:01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+)T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-γ) responses were associated with effector memory phenotypes, which were also detected in non-B*35:01-expressing T cells. However, only the B*35:01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+)T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity. IMPORTANCE: Dengue is an increasingly significant public health problem as its mosquito vectors spread over greater areas; no vaccines against the virus have yet been approved. An important step toward vaccine development is defining protective immune responses; toward that end, we here characterize the phenotype of the immunodominant T cell responses. These DENV-reactive T cells express high levels of the receptor programmed death 1 protein (PD-1), while those from disease-susceptible alleles do not. Not only does this represent a possible correlate of immunodominance, but it raises the hypothesis that PD-1 might be a regulator that prevents excessive damage while preserving antiviral function. Further, as this study employs distinct populations (Nicaraguan and Sri Lankan donors), we also confirmed that this pattern holds despite geographic and ethnic differences. This finding indicates that HLA type is the major determinant in shaping T cell responses.

Alleles↗

PubMed2023

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Mice↗

PubMed2026

First-in-human use of recombinant IL-7 to potentiate antigen-specific T cell therapy: a single patient case study.

Clinical trials of adoptive cellular therapy demonstrate that a key characteristic associated with durable responses is in vivo expansion and persistence of transferred T cells. Strategies to develop a less differentiated, stem/memory population in the infusion product and peri-infusional regimens to promote the maintenance of desired T cell states following adoptive transfer would be desirable. Endogenous T cell therapy studies have routinely achieved memory T cells enriched for expression of interleukin (IL)-7 receptor; to eliminate the conventional requirement for immunosuppressive lymphodepletion and its attendant life-threatening toxicities, we performed the first-in-human use of IL-7 in combination with adoptively transferred antigen-specific memory CD8 T cells in a patient with refractory metastatic uveal melanoma. Single-cell immune repertoire profiling of serial peripheral blood sampling revealed substantial in vivo proliferation and expansion of a stem cell memory population in the endogenous T cell therapy product that achieved a >79% predominance of total circulating T cells by 3 weeks post-infusion in this non-lymphodepleted recipient. Although the patient's disease ultimately progressed, these findings demonstrate safety and proof of concept for an IL-7 treatment regimen for expansion of adoptively transferred T cells in vivo and induced memory differentiation in a heavily pretreated patient with refractory solid malignancy.

Humans↗

PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗

PubMed2026

Distinct immune landscapes characterize highly versus minimally invasive brain metastases.

Brain metastases (BrMs) occur in approximately 30% of cancer patients, causing nearly one-fifth of cancer deaths. While immune checkpoint inhibitors (ICIs) benefit some BrM patients, responses remain highly variable. This variability partly reflects distinct histopathological growth patterns that include minimally invasive (MI) and highly invasive (HI) brain BrMs. Here we show that MI BrMs exhibit robust immune infiltration, whereas HI lesions are immunosuppressed. However, histological differentiation between MI and HI can be challenging because of subjective margin assessment. Here, using highly multiplexed spatial proteomics on 119 tumor sections from 46 patients with BrMs, we identify CHI3L1 as a key mediator of the immunosuppressive microenvironment in HI BrMs. In preclinical models, genetic deletion of CHI3L1 converts immune-cold metastases into lymphocyte-rich, ICI-responsive lesions infiltrated by granzyme B+ CD8+ T cells. In BrM patients treated with ICI, immunohistochemical quantification of CHI3L1 expression was a stronger predictor of ICI response than traditional MI/HI classification. Thus, CHI3L1 represents a promising biomarker and therapeutic target for BrMs.

Humans↗

PubMed2024

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

CD8-Positive T-Lymphocytes↗

PubMed2026

The N6-methyladenosine reader IGF2BP2 in T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm that lacks pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methyladenosine reader critically involved in oncogenesis. In this study, we observed consistently high expression of IGF2BP2 across common nodal PTCL subtypes in 3 independent external cohorts, which was further confirmed in our RNA-sequencing (RNA-seq) data set of 196 patients with newly diagnosed PTCL. Both in vitro and in vivo, IGF2BP2 promoted tumor cell growth and inhibited CD8+ T-cell infiltration within the tumor microenvironment. Mechanistically, IGF2BP2 bound to endosome-related genes (RAB4, VPS35, RAB9, and STAM) to maintain their stability, which resulted in enhanced endocytic activity and increased internalization of membrane proteins, and ultimately induced tumor cell proliferation and inhibition of CD8+ T-cell-mediated tumor cytotoxicity. The relationship between IGF2BP2 and endocytosis-associated genes was confirmed using RNA-seq data from patients with PTCL. IGF2BP2 as an upstream regulator of both tumor growth and immune suppression was further demonstrated in patient-derived xenograft models and a coculture system established using tumor samples from patients with PTCL and peripheral blood mononuclear cells. Notably, therapeutic targeting of IGF2BP2 with CWI1-2 suppressed endocytosis and impeded tumor growth in both cell lines and patient-derived xenograft models. Collectively, our findings highlight IGF2BP2 as a clinically relevant oncogenic driver in PTCL that integrates tumor-intrinsic growth signals with immune evasion through endocytosis-centered regulation, providing a novel therapeutic rationale for RNA modification-based strategies that concurrently target tumor cells and the tumor microenvironment.

Humans↗

PubMed2026

Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.

BACKGROUND: Functional exhaustion of tumor-infiltrating CD8+ T cells represents a hallmark of colorectal cancer (CRC) immunosuppression, though its mechanistic drivers remain elusive. Given the established correlation between CRC progression and stromal senescence characterized by pathological lipid accumulation and impaired immunity, we investigated whether and how senescent fibroblasts actively regulate CD8+ T cell dysfunction. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was conducted to unveil the diverse fibroblast populations and the significant lipid metabolism changes between senescent fibroblasts and non-senescent fibroblasts in human CRC specimens and adjacent normal mucosa. Machine-learning identified senescent fibroblasts with a distinct gene signature. Cell-cell communication analysis was used to evaluate the interactions between senescent fibroblasts and CD8+ T cells in colorectal cancer. Co-culture experiments were conducted among senescent fibroblasts, CD8+ T cells and patient-derived organoids of CRC (CRC-PDOs), with the results evaluated with high-content imaging and propidium iodide/Hoechst 33,342 staining. Flow cytometry, ELISA and lipid pulse-chase with BODIPY FL C16 were performed to detect the alterations of CD8+ T cell cytotoxic function and metabolic status. AOM/DSS-induced CRC mouse model was used to conduct in vivo validation to evaluate whether senolytics could suppress CRC progression. Patients from the Cancer Genome Atlas colorectal cancer cohort were stratified into CD36-high and CD36-low groups by median expression, and drug sensitivity for GDSC2 compounds was predicted computationally using the oncoPredict R package. RESULTS: ScRNA-seq demonstrated the specific cell population presence and divergence of senescent fibroblasts between neoplastic and histologically normal adjacent cell clusters in CRC. Random Forest was employed for cell senescence classification. Feature importance analysis identified five genes as key contributors to the model’s decision process. Cell-cell communication analysis revealed enhanced interactions between senescent fibroblasts and CD8+ T cells in CRC. Co-culture of senescent fibroblasts significantly impaired the cytotoxic functions of CD8+ T cells on CRC-PDOs, which was reflected by the declined proportions of granzyme B (GZMB) + and interferon gamma (IFNγ) + CD8+ T cells and enhanced viability of CRC-PDOs. Mechanistically, the co-culture with senescent fibroblasts promoted the lipid shuttling into CD8+ T cells to induce lipid peroxidation and downstream impairment of cytotoxicity. Furthermore, the inhibition of CD36, the specific scavenger receptor for lipid uptake of CD8+ T cells, effectively suppressed lipid transfer and peroxidation thereby preserving the effector functions of CD8+ T cells and ultimately promoting tumor apoptosis. Complementarily, in vivo senolytic treatment significantly suppressed CRC progression in AOM-DSS CRC mouse models. Top 12 therapeutic agents were identified significantly enhanced predicted efficacy in CD36-high tumors. CONCLUSIONS: Our study identified a substantial population of senescent fibroblasts in human CRC through single cell transcriptomics, machine-learning and clinical biopsies. These senescent fibroblasts impair CD8+ T cell-mediated killing of CRC-PDOs via CD36-dependent lipid transfer, suggesting senolytic targeting of stromal cells as a promising immunotherapeutic strategy for CRC.

Colorectal Neoplasms↗

PubMed2026

CD4+CD8+ double-positive T cells are associated with severity of tuberculosis.

BACKGROUND: Tuberculosis (TB) remains a global public health burden, and how immune cell subsets regulate host anti-TB immunity and disease progression remains incompletely understood. While previous studies have focused on single-positive (SP) T cells (CD4+ or CD8+) in TB pathogenesis, the association between CD4+CD8+ double-positive (DP) T cells and TB susceptibility, severity, and treatment outcomes have not been fully elucidated. This study aimed to investigate the relationship between DP T cells and other immune cell subsets with TB, and to explore the potential diagnostic and prognostic value of DP T cells in active TB. METHODS: A Genome-Wide Association Study (GWAS) was conducted to analyze 731 immune cell traits and a dataset encompassing 895 patients with TB. Subsequently, a cohort including 647 patients with active TB and 632 healthy controls was used to verify the findings of Mendelian randomization (MR). The correlation between the percentage of DP T cells in lymphocytes and TB severity, treatment efficacy, and Mycobacterium tuberculosis (Mtb)-specific IFN-γ production was evaluated. Finally, a random forest model incorporating the percentage of DP T cells in leukocytes and other peripheral blood parameters was constructed to distinguish severe from mild active TB. RESULTS: MR analysis suggested potential causal links between the percentage of DP T cells among peripheral leukocytes and TB status. Clinical sample validation showed that the percentage of peripheral DP T cell among leukocytes was significantly lower in patients with active TB than in healthy controls (P < 0.001), and was inversely correlated with disease severity. Additionally, the percentage of DP T cells in leukocytes was positively correlated with Mtb-specific antigen-stimulated IFN-γ production. Flow cytometric analysis demonstrated that DP T cells had a significantly higher frequency of IFN-γ-expressing cells compared to CD8+ SP T cells (P < 0.001). The constructed random forest model effectively distinguished severe from mild TB, with good diagnostic performance (AUC = 0.985). CONCLUSIONS: Our findings indicate that DP T cells are closely associated with TB severity, and are positively associated with Mtb-specific IFN-γ response. The percentage of peripheral DP T cells in leukocytes could serve as a potential non-invasive biomarker for TB severity stratification.

Humans↗