학술논문
CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours
Document Type
Author
Kruse, Bastian; Buzzai, Anthony C.; Shridhar, Naveen; Braun, Andreas D.; Gellert, Susan; Knauth, Kristin; Pozniak, Joanna; Peters, Johannes; Dittmann, Paulina; Mengoni, Miriam; van der Sluis, Tetje Cornelia; Höhn, Simon; Antoranz, Asier; Krone, Anna; Fu, Yan; Yu, Di, 1985; Essand, Magnus; Geffers, Robert; Mougiakakos, Dimitrios; Kahlfuss, Sascha; Kashkar, Hamid; Gaffal, Evelyn; Bosisio, Francesca M.; Bechter, Oliver; Rambow, Florian; Marine, Jean-Christophe; Kastenmüller, Wolfgang; Müller, Andreas J.; Tüting, Thomas
Source
Nature. 618(7967):1033-1040
Subject
Language
English
Abstract
Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1,2,3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4,5,6. 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 identified7,8,9,10. 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.