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IFNγ producing CD8⁺ T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

ABSTRACT: Tumors with reduced expression of MHC class I (MHC-I) molecules may be unrecognized by tumor antigen-specific CD8⁺ T cells and thus constitute a challenge for cancer immunotherapy. Here we monitored development of autochthonous melanomas in TiRP mice that develop tumors expressing a known tumor antigen as well as a red fluorescent protein (RFP) reporter knock in gene. The latter permits non-invasive monitoring of tumor growth by biofluorescence. One developing melanoma was deficient in cell surface expression of MHC-I, but MHC-I expression could be rescued by exposure of these cells to IFNγ. We show that CD8⁺ T cells specific for tumor antigen/MHC-I were efficient at inducing regression of the MHC-I-deficient melanoma, provided that the T cells were endowed with properties permitting their migration into the tumor and their efficient production of IFNγ. This was the case for CD8⁺ T cells transfected to express an active form of STAT5 (STAT5CA). The amount of IFNγ produced ex vivo from T cells present in tumors after adoptive transfer of the CD8⁺ T cells was correlated with an increase in surface expression of MHC-I molecules by the tumor cells. We also show that these CD8⁺ T cells expressed PD-1 and upregulated its ligand PDL-1 on melanoma cells within the tumor. Despite upregulation of this immunosuppressive pathway, efficient IFNγ production in the melanoma microenvironment was found associated with resistance of STAT5CA-expressing CD8⁺ T cells to inhibition both by PD-1/PDL-1 engagement and by TGFβ1, two main immune regulatory mechanisms hampering the efficiency of immunotherapy in patients.

SUBMITTER: Buferne M

PROVIDER: S-EPMC4404920 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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IFNγ producing CD8<sup>+</sup> T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

Buferne Michel M Chasson Lionel L Grange Magali M Mas Amandine A Arnoux Fanny F Bertuzzi Mélanie M Naquet Philippe P Leserman Lee L Schmitt-Verhulst Anne-Marie AM Auphan-Anezin Nathalie N

Oncoimmunology 20150201 2

Tumors with reduced expression of MHC class I (MHC-I) molecules may be unrecognized by tumor antigen-specific CD8<sup>+</sup> T cells and thus constitute a challenge for cancer immunotherapy. Here we monitored development of autochthonous melanomas in TiRP mice that develop tumors expressing a known tumor antigen as well as a red fluorescent protein (RFP) reporter knock in gene. The latter permits non-invasive monitoring of tumor growth by biofluorescence. One developing melanoma was deficient i ...[more]

PMID: 25949872

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Project description:IntroductionNaïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.MethodsHere we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.ResultsThe quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.DiscussionOverall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.

Dataset Information

IFNγ producing CD8⁺ T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

Publications

IFNγ producing CD8<sup>+</sup> T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

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Dataset Information

IFNγ producing CD8+ T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

Publications

IFNγ producing CD8<sup>+</sup> T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

IFNγ producing CD8⁺ T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.