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Published in: Cancer Immunology, Immunotherapy 11/2019

01-11-2019 | Lymphoma | Focussed Research Review

CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models

Authors: Bjarne Bogen, Marte Fauskanger, Ole Audun Haabeth, Anders Tveita

Published in: Cancer Immunology, Immunotherapy | Issue 11/2019

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Abstract

It is well recognized that CD4+ T cells may play an important role in immunosurveillance and immunotherapy against cancer. However, the details of how these cells recognize and eliminate the tumor cells remain incompletely understood. For the past 25 years, we have focused on how CD4+ T cells reject multiple myeloma cells in a murine model (MOPC315). In our experimental system, the secreted tumor-specific antigen is taken up by tumor-infiltrating macrophages that process it and present a neoepitope [a V region-derived idiotypic (Id) peptide] on MHC class II molecules to Th1 cells. Stimulated Th1 cells produce IFNγ, which activates macrophages in a manner that elicits an M1-like, tumoricidal phenotype. Through an inducible nitric oxide synthetase (iNOS)-dependent mechanism, the M1 macrophages secrete nitric oxide (NO) that diffuses into neighboring tumor cells. Inside the tumor cells, NO-derived reactive nitrogen species, including peroxynitrite, causes nitrosylation of proteins and triggers apoptosis by the intrinsic apoptotic pathway. This mode of indirect tumor recognition by CD4+ T cells operates independently of MHC class II expression on cancer cells. However, secretion of the tumor-specific antigen, and uptake and MHCII presentation on macrophages, is required for rejection. Similar mechanisms can also be observed in a B-lymphoma model and in the unrelated B16 melanoma model. Our findings reveal a novel mechanism by which CD4+ T cells kill tumor cells indirectly via induction of intratumoral cytotoxic macrophages. The data suggest that induction of M1 polarization of tumor-infiltrating macrophages, by CD4+ T cells or through other means, could serve as an immunotherapeutic strategy.
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Metadata
Title
CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models
Authors
Bjarne Bogen
Marte Fauskanger
Ole Audun Haabeth
Anders Tveita
Publication date
01-11-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 11/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-019-02374-0

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