title: The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas.
abstract: Tryptophan metabolism is a key process that shapes the immunosuppressive tumor microenvironment. The two rate-limiting enzymes that mediate tryptophan depletion, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO), have moved into the focus of research and inhibitors targeting IDO and TDO have entered clinical trials. Local tryptophan depletion is generally viewed as the crucial immunosuppressive mechanism. In T cells, the kinase general control non-derepressible 2 (GCN2) has been identified as a molecular sensor of tryptophan deprivation. GCN2 activation by tryptophan depletion induces apoptosis and mitigates T cell proliferation. Here, we investigated whether GCN2 attenuates tumor rejection in experimental B16 melanoma using T cell-specificGcn2knockout mice. Our data demonstrate that GCN2 in T cells did not affect immunity to B16 tumors even when animals were treated with antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA4). GCN2-deficient gp100 TCR-transgenic T cells were equally effective as wild-type pmel T cells against gp100-expressing B16 melanomas after adoptive transfer and gp100 peptide vaccination. Even augmentation of tumoral tryptophan metabolism in B16 tumors by lentiviral overexpression ofTdodid not differentially affect GCN2-proficient vs. GCN2-deficient T cellsin vivo. Importantly, GCN2 target genes were not upregulated in tumor-infiltrating T cells. MALDI-TOF MS imaging of B16 melanomas demonstrated maintenance of intratumoral tryptophan levels despite high tryptophan turnover, which prohibits a drop in tryptophan sufficient to activate GCN2 in tumor-infiltrating T cells. In conclusion, our results do not suggest that suppression of antitumor immune responses by tryptophan metabolism is driven by local tryptophan depletion and subsequent GCN2-mediated T cell anergy.
authors.affiliation: DKTK CCU Neuroimmunology and Brain Tumor Immunology, DKFZ , Heidelberg, Germany.
authors.forename: Jana K
authors.identifier: 0000-0002-4700-272X
authors.initials: JK
authors.lastname: Sonner
authors.affiliation: DKTK CCU Neuroimmunology and Brain Tumor Immunology, DKFZ , Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Deumelandt
authors.affiliation: DKTK CCU Neuroimmunology and Brain Tumor Immunology, DKFZ , Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ott
authors.affiliation: DKTK CCU Neurooncology, DKFZ , Heidelberg, Germany.
authors.forename: Carina M
authors.initials: CM
authors.lastname: Thomé
authors.affiliation: DKTK CCU Neuroimmunology and Brain Tumor Immunology, DKFZ , Heidelberg, Germany.
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Rauschenbach
authors.affiliation: Centre for Applied Research "Applied Biomedical Mass Spectrometry" (ABIMAS), Hochschule Mannheim , Mannheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Centre for Applied Research "Applied Biomedical Mass Spectrometry" (ABIMAS), Hochschule Mannheim , Mannheim, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Munteanu
authors.affiliation: Junior Group Brain Cancer Metabolism, DKFZ , Heidelberg, Germany.
authors.forename: Soumya
authors.initials: S
authors.lastname: Mohapatra
authors.affiliation: Junior Group Brain Cancer Metabolism, DKFZ , Heidelberg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Adam
authors.affiliation: Research Group Immune Tolerance, DKFZ , Heidelberg, Germany.
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Hofer
authors.affiliation: Research Group Immune Tolerance, DKFZ , Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Feuerer
authors.affiliation: Junior Group Brain Cancer Metabolism, DKFZ, Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
authors.affiliation: Centre for Applied Research "Applied Biomedical Mass Spectrometry" (ABIMAS), Hochschule Mannheim , Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.affiliation: DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: DKTK CCU Neuroimmunology and Brain Tumor Immunology, DKFZ, Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Department of Neurology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
keywords: AHR; CHOP; GCN2; IDO; T cells; TDO; tryptophan