An IL-34–IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression

Interleukin-9 Receptor Signaling Promotes an Immunosuppressive Tumor Immune Microenvironment in Oncogene-Driven Non-Small Cell Lung Cancer 2264775

Non-small cell lung cancer (NSCLC), particularly oncogene-driven subtypes, remains a leading cause of cancer-related mortality, underscoring the urgent need for novel immunotherapies that effectively target the tumor immune microenvironment (TIME). The interleukin-9 receptor (IL-9R) signaling pathway is understudied but emerging evidence, including our previous work, suggests a pro-tumoral role in NSCLC by promoting an immunosuppressive TIME. We hypothesize that IL-9R signaling fosters immunosuppression within the lung TIME of NSCLC and that its blockade represents a viable therapeutic strategy to restrain tumor progression. Using a K-rasLSL-G12D/+; p53fl/fl (KP) mouse model of NSCLC, we compared tumor development between IL-9R knockout (Il9r—/—) and wild-type (WT) mice. Flow cytometry was performed to analyze lung-infiltrating immune cell populations. Bone marrow chimera experiments were conducted to assess the contribution of IL-9R signaling in hematopoietic versus non-hematopoietic compartments. Il9r—/— tumor-bearing mice exhibited significantly reduced lung tumor burden compared to WT controls. Flow cytometric analysis revealed that IL-9R deficiency decreased the accumulation of immunosuppressive myeloid cells, including neutrophils/granulocytic MDSCs and arginase 1+ macrophages, while enhancing pro-inflammatory cytokine production (IFN-γ, TNF-α, and IL-17) by T cells. Bone marrow chimera studies showed that WTmice reconstituted with Il9r—/— bone marrow exhibited reduced tumor burden, whereas Il9r—/— recipients reconstituted with WTbone marrow displayed tumor progression comparable to WT controls, indicating that IL-9R signaling in hematopoietic cells drives tumor-promoting immunosuppression. Our findings identify IL-9R signaling as a critical regulator of the immunosuppressive lung TIME and suggest that targeting the IL-9R pathway may represent a promising immunotherapeutic strategy for oncogene-driven NSCLC. The Indiana Clinical & Translational Sciences Institute (CTSI) Biomedical Research Grant Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

IL-26-driven epigenetic remodeling promotes immune evasion in colorectal cancer

Cancer cells acquire malignant traits through epigenetic remodeling driven by inflammatory secretomes in the tumor microenvironment. However, how immune-derived inflammatory factors regulate cancer cell epigenetics remains poorly understood. Here, we show that IL-26 produced by tumor-specific type 17 T cells acts as a key mediator of epigenetic reprogramming associated with cancer malignancy. We identify selective accumulation of IL-26–expressing T cells in colorectal tumors resistant to immune checkpoint blockade therapy. IL-26 functions as a noncanonical cytokine by translocating into the nucleus of tumor cells, where it directly binds STAT1 and forms transcriptional complexes with NF-κB and AP-1. Nuclear IL-26 induces a transcriptionally active chromatin state characterized by BRD4 and H3K27ac enrichment, resulting in upregulation of CXCL chemokines. This process promotes neutrophil infiltration and enhances immune evasion and tumor progression by suppressing CD8 + T cell responses. Together, these findings support a model in which tumor-specific type 17 T cells directly reprogram cancer cell epigenetics through IL-26, reshaping the tumor immune microenvironment to promote immune evasion. How immune-derived inflammatory factors shape cancer cell epigenetics to promote immune checkpoint blockade resistance remains to be explored. The authors here show that IL-26 from type 17 T cells induces BRD4-dependent epigenetic remodeling in cancer-cell nuclei, thereby promoting malignant progression and immune evasion.

T cells are critical for pre-metastatic niche formation through the STAT3/IL-17 axis

Abstract Background Pre-metastatic niches composed of mainly myeloid cells are recognized as critical for tumor metastasis. However, whether adaptive immune cells also play an important role in pre-metastatic niche formation remains to be explored. Methods CD4+ T cell accumulation in tumor-free lung tissues from mice bearing subcutaneous mouse tumors was detected by immunofluorescence/confocal microscopy. Tumor-conditioned media (TCM) from MB49-S1pr1high mouse bladder tumor cells or ID8 ovarian tumor cells were administered to tumor-free mice to induce pre-metastatic niche formation. We used mice lacking functional Signal Transducer and Activator of Transcription 3 (STAT3) in T cells and Il17a‒/‒ mice to investigate the roles of STAT3 and interleukin (IL)-17. In vivo time-course experiments were performed to assess whether CD4+ T cell clusters contribute to CD11b+ pre-metastatic clusters. CD4+ T cell migration and chemokine receptor expression assays were employed to identify tumor factors driving CD4+ T cell recruitment. A co-culture system with human MRC-5 lung fibroblasts, healthy donor-derived CD4+ T cells, myeloid cells, and TCM derived from human cancer cells was used to evaluate CD4+ T cell-driven fibroblast activation and IL-17A dependency for myeloid cell migration. Microscopic analyses were performed to confirm CD4+ T cell clusters in tumor-free lymph node tissues from patients with prostate cancer and postmortem lung and liver specimens from patients with ovarian cancer. Results We demonstrate that CD4+ T cells accumulate in tumor-free lungs and promote tumor metastasis in mouse models. CD4+ T-cell pre-metastatic niche formation requires STAT3, which regulates Th17 CD4+ T cells. TCM drives IL-6-dependent CCR4/CCR6 upregulation on naive CD4+ T cells. CD4+ T cell clusters contribute to myeloid cell accumulation, and ablating STAT3 in T cells abrogates both T cell and myeloid cluster formation. IL-17 inhibition reduces myeloid lung infiltration. In human co-cultures, CD4+ T cells amplify TCM-induced fibroblast pre-metastatic niche-like activation and myeloid recruitment in an IL-17A-dependent manner. CD4+ and IL-17+ or p-STAT3+ clusters were also detected in non-metastatic tissues from patients with several cancers. Conclusions CD4+ T cells form pre-metastatic niches through the STAT3-IL-17 axis, contributing to myeloid cell cluster formation, in part through amplifying fibroblast pre-metastatic niche-like activation. STAT3 and IL-17 in CD4+ T cells therefore are important for pre-metastatic niche formation and metastasis.

LTBP4 deficiency induces MRC1+/CD44+ macrophages to drive cancer progression in preclinical colorectal cancer models.

The tumor microenvironment is crucial for cancer progression, but the mechanisms underlying the tumor-immune cell interactions in it remain poorly understood. Here, we identified latent transforming growth factor-β (TGFβ) binding protein 4 (LTBP4) deficiency in colorectal cancer (CRC) as a critical driver that reprogrammed tumor-associated macrophages (TAMs) and induced a distinct subset, which promoted tumor progression by coordinating immune evasion and extracellular matrix (ECM) remodeling. Clinically, LTBP4 deficiency correlated with CRC progression and poor patient survival. Ltbp4 knockout markedly promoted tumor growth and metastasis in immunocompetent mice, an effect attenuated in immunodeficient hosts, establishing the essential role of host immunity in mediating the effects of LTBP4 deficiency. Single-cell RNA sequencing revealed that LTBP4 deficiency induced a mannose receptor C-type 1-positive (MRC1+)/CD44+ TAM subset and correlated with reduced CD8+ T cell infiltration. Mechanistically, LTBP4 deficiency increased active TGFβ1 levels, which acted in a paracrine manner to up-regulate MRC1 in TAMs, whereas autocrine signaling induced HAS2 (hyaluronan synthase 2) expression and hyaluronan production to increase CD44. CD44 signaling in TAMs up-regulated matrix metalloproteinases for collagen degradation, whereas MRC1 mediated collagen internalization, cooperatively remodeling the ECM to facilitate tumor invasion. The TGFβ1-driven MRC1+/CD44+ TAMs further suppressed CD8+ T cell function by diminishing the C-X-C motif chemokine ligand 16-C-X-C motif chemokine receptor 6 (CXCL16-CXCR6) axis. Therapeutically, targeted depleting MRC1+/CD44+ TAMs enhanced the efficacy of PD-1 (programmed cell death-1) blockade in LTBP4-deficient tumors. Our study positions LTBP4 as a key modulator of tumor progression and reveals a therapeutic strategy for LTBP4-deficient CRC.

Aging-associated regulatory B-like cells establish a lung-selective immunosuppressive niche to promote pulmonary metastasis

Stk11 loss in lung adenocarcinoma increases tumor CXCL16 and is associated with an expansion of Areg+ CXCR6+ IL-17-producing γδ T cells 2310280

gd T cells have been shown to both promote tumor growth/metastasis and to efficiently kill tumor cells. These contrasting roles have been attributed to their different functional subsets, with gdT1 cells being associated with anti-tumor immunity, while gdT17 cells are associated with tumor growth and metastasis. However, the factors that regulate the activation and expansion of these functional subsets, as well as the mechanisms through which they regulate tumor growth are still unclear. To investigate these questions, we developed a novel inducible model of Scgb1a1-linked Kras-driven lung adenocarcinoma with or without an Stk11 co-mutation and used multi-color flow cytometry to characterize the tumor-immune microenvironment and single-cell RNAseq to examine both the gd T cells and the tumor lung epithelium. Upon tumor induction KrasG12D/Stk11fl (KS) mice exhibited significantly higher tumor burden and faster disease progression than KrasG12D (K) mice. The more rapid disease progression in these mice was associated with a significant increase in Vg4 and Vg6 gdT17 cells, but not Vg1 gdT1 cells. scCITEseq revealed significant changes in the transcriptional diversity of the KS lung gdT17 cells that was associated with an expansion of an Areg+ Vg6 gdT17 subset. There was no significant difference, however, in gd T cell proliferation. Investigation of the Scgb1a1+ lung epithelium revealed that KS tumors upregulate the expression of numerous immune-relevant chemokines and cytokines, including Cxcl16. When cultured in vitro, tumor cells but not healthy epithelial cells from KS mouse lungs produced significant levels of CXCL16. Finally, we demonstrated that lung gdT17, but not gdT1 cells, express the CXCL16 receptor CXCR6. Taken together, these data show that tumor-intrinsic Stk11 loss in lung adenocarcinoma is associated with an expansion of lung gdT17 cells and supports a model in which these pro-tumor cells are recruited to the KS mouse lung via a CXCL16-CXCR6 axis. n/a Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)