Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5 (ALK5) mice reject tumors in high proportions, dependent on CD8 T cells. ALK5 mice have more tumor-infiltrating effector CD8 T cells, with more cytotoxic capacity. ALK5-deficient CD8 T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8 T cells, thereby limiting their trafficking into tumors.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145847 | PMC |
| http://dx.doi.org/10.1038/s41467-020-15404-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The role of the microbiome in skin cancer development and treatment.
Curr Opin Oncol
January 2025
San Roque Hospital, Lanzarote, Spain.
Purpose Of Review: Recent research underscores the significant influence of the skin and gut microbiota on melanoma and nonmelanoma skin cancer (NMSC) development and treatment outcomes. This review aims to synthesize current findings on how microbiota modulates immune responses, particularly enhancing the efficacy of immunotherapies such as immune checkpoint inhibitors (ICIs).
Recent Findings: The microbiota's impact on skin cancer is multifaceted, involving immune modulation, inflammation, and metabolic interactions.
Single-Cell Sequencing of Peripheral Blood Mononuclear Cells Reveals Immune Landscape of Monkeypox Patients with HIV.
Emerg Microbes Infect
January 2025
State Key Laboratory of Experimental Hematology, Department of Physiology and Pathophysiology, Tianjin Medical University, Heping, Tianjin, 300070 China.
The monkeypox (MPXV) outbreak in 2022 is more prevalent among individuals with human immunodeficiency virus (HIV). While it is plausible that HIV-induced immunosuppression could result in a more severe progression, the exact mechanisms remain undetermined. To better understand the immunopathology of MPXV in patients with and without HIV infection, we employed single-cell RNA sequencing (scRNA-seq) to analyze peripheral blood mononuclear cells (PBMCs) from 6 patients hospitalized for MPXV, 3 of whom had HIV infection (HIV antibody positive & HIV RNA level below the detection limit), and 3 patients only infected with MPXV (HIV-).
View Article and Find Full Text PDFNK Count and Natural Cytotoxicity in Immune Nonresponders Versus Responders Living With HIV.
J Med Virol
February 2025
Infectious Diseases Department, University Hospital Montpellier & INSERM U1175, University Montpellier, Montpellier, France.
Despite viral suppression with antiretroviral therapy, immune nonresponders (INR) among people living with HIV (PLWH) still have a higher risk of developing AIDS-related and non-AIDS-related complications. Our study aimed to investigate the phenotype and functions of Natural Killer (NK) cells in INR, to better understand underlying mechanisms of immune nonresponse. Our cross-sectional study included PLWH aged over 45 with an undetectable HIV viral load sustained for at least 2 years.
View Article and Find Full Text PDFCircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.
Neuro Oncol
January 2025
Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.
Background: Glioblastoma stem cells (GSCs) and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in glioma microenvironment.
View Article and Find Full Text PDFImmune-Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges.
Liver Int
February 2025
APHP, Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm, Unité 1193, Université Paris-Saclay, FHU Hepatinov, Villejuif, France.
Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!