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Results for “Tumor-infiltrating fibroblast”

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PubMed2026

IDH3-dependent mitochondrial function in stromal fibroblasts suppresses malignant tumor growth.

Malignant solid tumors comprise not only cancer cells but also diverse non-cancerous stromal cells that shape the tumor microenvironment. The tricarboxylic acid (TCA) cycle has an overarching presence in providing substrates needed to drive the electron transport chain and, ultimately, ATP synthesis. However, it remains unclear which stromal cell lineages influence tumor growth through TCA-dependent mitochondrial function, and whether such activities act in a tumor-promoting or tumor-suppressive manner. Isocitrate dehydrogenase 3 (IDH3), a rate-limiting TCA cycle enzyme that generates NADH to support mitochondrial respiration, provides a genetic entry point to interrogate mitochondrial TCA-dependent function in stromal cells. In this study, we established a mouse model in which tamoxifen administration induces CreERT2-dependent knockout of the α subunit of IDH3 (IDH3α) in all somatic cells. Using this model with transplantation of Idh3a-intact murine cancer cells, we found that host Idh3a deficiency accelerated growth of murine MC38 tumors in a cancer cell line-dependent manner. Bone marrow chimera experiments indicated that hematopoietic lineages were not responsible for this phenotype, suggesting a contribution from tissue-resident non-hematopoietic stromal cells that are not replaced by bone marrow transplantation. Single-cell RNA sequencing of human tumor specimens revealed broad IDH3A expression across multiple tumor microenvironment compartments, including fibroblasts. Consistently, in vitro co-culture assays demonstrated that Idh3a-intact, but not Idh3a-KO, fibroblasts suppressed cancer cell proliferation in a contact-dependent manner. Together, these findings identify IDH3α-dependent mitochondrial function in fibroblasts as a critical determinant of tumor progression and suggest that stromal mitochondrial metabolism represents an important axis for modulating tumor behavior.

Cancer↗

PubMed2025

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment. EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin. RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs. CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment. TRIAL REGISTRATION NUMBER: NCT03991403.

Aged↗

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↗

PubMed2025

Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.

Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Humans↗

PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗

PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗