Dataset Information

CD4⁺ T cell-induced inflammatory cell death controls immune-evasive tumours.

ABSTRACT: Most clinically applied cancer immunotherapies rely on the ability of CD8⁺ cytolytic T cells to directly recognize and kill tumour cells^1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment^4-6. The ability of CD4⁺ effector cells to contribute to antitumour immunity independently of CD8⁺ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified^7-10. Here, we describe a mechanism whereby a small number of CD4⁺ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8⁺ T cell targeting. The CD4⁺ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II⁺CD11c⁺ antigen-presenting cells. We show that T helper type 1 cell-directed CD4⁺ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4⁺ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4⁺ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8⁺ T cells and natural killer cells and advance cancer immunotherapies.

SUBMITTER: Kruse B

PROVIDER: S-EPMC10307640 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours.

Kruse Bastian B Buzzai Anthony C AC Shridhar Naveen N Braun Andreas D AD Gellert Susan S Knauth Kristin K Pozniak Joanna J Peters Johannes J Dittmann Paulina P Mengoni Miriam M van der Sluis Tetje Cornelia TC Höhn Simon S Antoranz Asier A Krone Anna A Fu Yan Y Yu Di D Essand Magnus M Geffers Robert R Mougiakakos Dimitrios D Kahlfuß Sascha S Kashkar Hamid H Gaffal Evelyn E Bosisio Francesca M FM Bechter Oliver O Rambow Florian F Marine Jean-Christophe JC Kastenmüller Wolfgang W Müller Andreas J AJ Tüting Thomas T

Nature 20230614 7967

Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recog ...[more]

PMID: 37316667

Similar Datasets

Project description:BackgroundHIV-2 infection is characterised by a longer asymptomatic phase and slower AIDS progression than HIV-1 infection. Identifying unique immune signatures associated with HIV-2 pathogenesis may thus provide therapeutically useful insight into the management of HIV infection. This study examined the dynamics of the CD4+T cell compartment, critical in disease progression, focussing on chronic HIV-2 and HIV-1 infected individuals at various stages of disease progression.MethodsA total of 111 participants including untreated and treated HIV infected individuals and seronegative individuals were enrolled in this study. The relative proportion of CD4+T cell subsets, expressing CD25 (IL-2Rα) and CD127 (IL-7R), in HIV infected individuals and seronegative controls were assessed by multiparametric flow cytometry. Additionally, levels of immune activation and cytotoxic T lymphocytes in both the CD4+T and CD8+T cell compartments was evaluated.ResultsBoth treated and untreated, HIV-1 and HIV-2 infected individuals showed apparent dysregulation in CD4+ T cell subset frequency that was associated with disease progression. Furthermore, longitudinal sampling from a group of HIV-1 infected individuals on virologically effective ART showed no significant change in dysregulated CD4+T cell subset frequency. For both ART naïve and receiving groups associations with disease progression were strongest and significant with CD4+ T cell subset frequency compared to per cell expression of IL-2Rα and IL-7Rα. In untreated HIV-2 infected individuals, T cell activation was lower compared to ART naïve HIV-1 infected individuals and higher than seronegative individuals. Also, the level of Granzyme-B expressing circulating T cells was higher in both ART-naïve HIV-1 and HIV-2 infected individuals compared to seronegative controls.ConclusionDysregulation of IL-2 and IL-7 homeostasis persists in CD4+T cell subsets irrespective of presence or absence of viremia or antiretroviral therapy in HIV infection. Furthermore, we report for the first time on levels of circulating Granzyme-B expressing CD4+T and CD8+T cells in chronic HIV-2 infection. Lower immune activation in these individuals indicates that persistent immune activation driven CD4+T cell depletion, as observed in untreated HIV-1 infected individuals, may not be as severe and provides evidence for a disparate pathogenesis mechanism. Our work also supports novel immunomodulatory therapeutic strategies for both HIV-1 and HIV-2 infection.

Dataset Information

CD4⁺ T cell-induced inflammatory cell death controls immune-evasive tumours.

Publications

CD4<sup>+</sup> T cell-induced inflammatory cell death controls immune-evasive tumours.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets