IL-16 promotes anti-tumor immunity via establishing a Th1-dominant tumor microenvironment [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1039765 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26806935_1.fastq.gz | Fastqsanger.gz | |||
| SRR26806935_2.fastq.gz | Fastqsanger.gz | |||
| SRR26806936_1.fastq.gz | Fastqsanger.gz | |||
| SRR26806936_2.fastq.gz | Fastqsanger.gz | |||
| SRR26806937_1.fastq.gz | Fastqsanger.gz |
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Project description:Overcoming immunosuppression in tumor microenvironment (TME) is fundamental to the development of novel cancer immunotherapies. Herein, we revealed an unrecognized role of IL-16 in shaping anti-tumor immunity. Compared with healthy subjects, cancer patients had impaired production of IL-16, which was correlated with inferior patient prognosis. In multiple murine cancer models, IL-16 administration augmented the anti-tumor immune responses and thus restrained tumor growth. Mechanistically, IL-16 potentiated the polarization of T helper 1 (Th1) cells and the production of their effector cytokine IFN-γ, Mechanistically, IL-16 blocked glutamine catabolism by downregulating glutaminase (GLS) expression in CD4+ T cells. The IL-16-established Th1 tumor microenvironment further increased the expression of CXCR3 ligands in tumor-associated macrophages, which improved the therapeutic efficacy of immune checkpoint blockade (ICB). In cancer patients who received anti-PD1 therapy, high IL-16 levels correlated with better responsiveness. Finally, we found that the impaired production of histamine by mast cells was a causative factor for IL-16 downregulation in TME. Thus, IL-16 administration may serve as a potential approach to augment anti-tumor immunity, and also improve the outcome of ICB therapy in cancer patients. Collectively, we provided new insights into the biological function of IL-16 and thus highlighted its potential clinical value in cancer immunotherapy.
2025-01-20 | GSE247579 | GEO
Project description:Overcoming immunosuppression in tumor microenvironment (TME) is crucial for the development of novel cancer immunotherapies. In this study, we revealed a previously unrecognized role of IL-16 in shaping anti-tumor immunity. Compared to healthy individuals, cancer patients exhibited impaired production of IL-16, which was associated with inferior patient prognosis. In multiple murine cancer models, IL-16 administration augmented the anti-tumor immune responses and thus restrained tumor growth. Further investigation uncovered that IL-16 potentiated the polarization of T helper 1 (Th1) cells and the production of their effector cytokine IFN-γ. Mechanistically, IL-16 inhibited glutamine catabolism by downregulating the expression of glutaminase (GLS) in CD4+ T cells. The establishment of IL-16-dependent Th1 tumor microenvironment further increased the expression of CXCR3 ligands in tumor-associated macrophages (TAMs), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). In cancer patients who received anti-PD1 therapy, higher levels of IL-16 were correlated with better responsiveness. Finally, we found that the impaired production of histamine by mast cells was a contributing factor to the downregulation of IL-16 in TME. Therefore, IL-16 could potentially be utilized as a therapeutic approach to augment anti-tumor immunity, and improve the outcome of ICB therapy in cancer patients. Collectively, our research provided new insights into the biological function of IL-16, emphasizing its potential clinical significance in cancer immunotherapy.
2025-01-20 | GSE254991 | GEO
Project description:Interleukin-16 Establishes a Th1-dominant Tumor Immune Microenvironment And Potentiates Immune Checkpoint Therapies [scRNA-Seq]
| PRJNA1072985 | ENA
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy by intervening the M2-like TAM/Th1-Treg axis.
2024-11-07 | GSE251735 | GEO
Project description:Cryo-thermal therapy has been proven to be a promising novel systemic strategy for advanced breast cancer, resulting in higher incidence of tumor regression and enhanced remission of metastasis. The mechanism by which such strategy boosts the anti-tumor activity remains unclear. To gain a system-wide understanding of the anti-tumor response, here we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare the N-glycoproteome changes following treatment or not in 94 serum samples over 8 time points. We quantified 231 high confident N-glycosylated serum proteins in total using iTRAQ labeling shotgun proteomic. 53 of them showed significant regulatory patterns over time course, in which we identified acute phase response as the most enhanced pathway and markedly distinguished in the hierarchical proteome profile. We therefore investigated the function of acute response in tumoricidal effect using quantitative parallel reaction monitoring proteomics and flow cytometry upon 23 out of 53 significant proteins. We found that cryo-thermal therapy reshaped the tumor chronic inflammatory microenvironment to an ‘acute’ phenotype, accompanying ‘acute’ and markedly high expression of acute phase proteins and their key upstream regulator -interleukin 6. Such IL-6 mediated ‘acute’ phenotype drove the tumor site from a Th2 immunosuppressive, pro-tumorigenic to a Th1 immunostimulatory, tumouricidal phenotype, inducing a switch from IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN –γand IL-12 production, skewing to complement system activation and CD86+MHCII+ dendritic cells maturation, and enhancing the proliferation of Th1 memory cells. We also found an increased production of tumor metastatic inhibitors under such ‘acute’ environment, favoring the anti-metastatic effect. In this study, we revealed that IL-6 mediated ‘acute’ inflammatory profile played a key role to suppress immunosuppression and wake up the anti-tumor activity, recovering host metabolism and physiology. This could guide us a better understanding to improve this cancer treatment for better therapeutic effect.
2016-05-12 | PXD003136 | Pride
Project description:Expression data from mouse tumor-specific CD4+ T cells The central role of tumor-specific Th1 cells in fighting cancer is becoming increasingly appreciated. However, little is known about how these cells are generated in vivo. Here, we used flow cytometry and gene expression microarrays to characterize the primary activation and Th1 differentiation of naïve tumor-specific CD4+ T cells in a mouse model for cancer immunosurveillance. We took advantage of T cell receptor-transgenic mice where CD4+ T cells recognize a tumor-specific antigen secreted by the major histocompatibility complex (MHC) class II-negative MOPC315 myeloma. Cancer cells were injected subcutaneously and T cell activation was analyzed in draining lymph nodes and at the incipient tumor site at day +8. After activation and migration to the incipient tumor site, tumor-specific CD4+ T cells had 29 up-regulated molecules (CD2, CD5, CD11a, CD18, CD25, CD28, CD44, CD45, CD49d, CD51, CD54, CD69, CD71, CD83, CD86, CD90, CD95, CD102, CD122, CD153, CD166, CD200, CD249, CD254, CD274, CD279, Ly6C, MHC class I, and CCR7) and 5 down-regulated molecules (CD27, CD31, CD45RB, CD62L, and CD126) on the surface. The activated CD4+ T cells produced interferon , a cytokine consistent with Th1 polarization, and also interleukin 2 (IL-2), IL-3, IL-10, and tumor necrosis factor . Activation of naïve tumor-specific CD4+ T cells in draining lymph node resulted in the up-regulation of 609 genes and down-regulation of 284 genes. Bioinformatics analysis of genes differentially expressed identified functional pathways related to tumor-specific Th1 cell activation. This study may represent a useful resource to guide the development of Th1-based immunotherapy for cancer. TCR-transgenic SCID mice (n = 12-15) were injected s.c. on the flank with 10(5) MOPC315 cells suspended in 250 µl ice-cold growth factor-reduced Matrigel. At day +8, draining axillary LN were dissected out and pooled, single-cell suspensions were made and staining with mAb was carried out. Activated tumor-specific CD4+ GB113+ T cells were sorted by FACSAria (≥ 95% pure) in three independent experiments. Naïve tumor-specific CD4+ control T cells were obtained from pooled LN from naive TCR-transgenic SCID mice and treated identically in two independent experiments.
2013-05-15 | E-GEOD-46453 | biostudies-arrayexpress
Project description:The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered tumor-promoting. In contrast, the exact nature of protective antitumor immunity remains obscure. In this study, we have quantified locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumor-specific CD4+ T cells was consistently associated with elevated local levels of both proinflammatory (IL-1aplha, IL-1beta, and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-alpha, IL-2, IL-12). Cancer eradication was achieved by a collaboration between tumor-specific Th1 cells and tumor-infiltrating, antigen-presenting macrophages. Th1 cells induced secretion of IL-1? and IL-6 by macrophages. Th1-derived interferon-? was shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumor-specific Th1 cells, may prevent rather than promote cancer. Tumoricidal macrophages were isolated from Idiotype-specific TCR-transgenic SCID mice injected with MOPC315-containing Matrigel. Control macrophages were obtained from TCR-transgenic SCID mice injected with Matrigel containing antigen-loss MOPC315.
2011-03-15 | E-GEOD-26912 | biostudies-arrayexpress
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy.
2024-11-07 | GSE252052 | GEO
Project description:Expression data from mouse tumor-specific CD4+ T cells The central role of tumor-specific Th1 cells in fighting cancer is becoming increasingly appreciated. However, little is known about how these cells are generated in vivo. Here, we used flow cytometry and gene expression microarrays to characterize the primary activation and Th1 differentiation of naïve tumor-specific CD4+ T cells in a mouse model for cancer immunosurveillance. We took advantage of T cell receptor-transgenic mice where CD4+ T cells recognize a tumor-specific antigen secreted by the major histocompatibility complex (MHC) class II-negative MOPC315 myeloma. Cancer cells were injected subcutaneously and T cell activation was analyzed in draining lymph nodes and at the incipient tumor site at day +8. After activation and migration to the incipient tumor site, tumor-specific CD4+ T cells had 29 up-regulated molecules (CD2, CD5, CD11a, CD18, CD25, CD28, CD44, CD45, CD49d, CD51, CD54, CD69, CD71, CD83, CD86, CD90, CD95, CD102, CD122, CD153, CD166, CD200, CD249, CD254, CD274, CD279, Ly6C, MHC class I, and CCR7) and 5 down-regulated molecules (CD27, CD31, CD45RB, CD62L, and CD126) on the surface. The activated CD4+ T cells produced interferon , a cytokine consistent with Th1 polarization, and also interleukin 2 (IL-2), IL-3, IL-10, and tumor necrosis factor . Activation of naïve tumor-specific CD4+ T cells in draining lymph node resulted in the up-regulation of 609 genes and down-regulation of 284 genes. Bioinformatics analysis of genes differentially expressed identified functional pathways related to tumor-specific Th1 cell activation. This study may represent a useful resource to guide the development of Th1-based immunotherapy for cancer.
2013-05-15 | GSE46453 | GEO
Project description:The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered tumor-promoting. In contrast, the exact nature of protective antitumor immunity remains obscure. In this study, we have quantified locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumor-specific CD4+ T cells was consistently associated with elevated local levels of both proinflammatory (IL-1aplha, IL-1beta, and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-alpha, IL-2, IL-12). Cancer eradication was achieved by a collaboration between tumor-specific Th1 cells and tumor-infiltrating, antigen-presenting macrophages. Th1 cells induced secretion of IL-1? and IL-6 by macrophages. Th1-derived interferon-? was shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumor-specific Th1 cells, may prevent rather than promote cancer.
2011-03-15 | GSE26912 | GEO