CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165278 | GEO | 2021/03/08
REPOSITORIES: GEO
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Project description:Here, we report the immune-mediated mechanisms underlying the improved activity of immune checkpoint blockade in glycolysis-defective tumor models.
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Project description:CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors
| PRJNA688711 | ENA
Project description:CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors.
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Project description:Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells1. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis1. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8+ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (Treg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of Treg cells is dependent on Treg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with Treg cell function in the presence of glucose.
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Project description:Immune checkpoint inhibitors such as anti-CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti-CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti-CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti-CTLA-4 antibodies and possibly other antibody-based immunotherapies.
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Project description:Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+ regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.
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Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
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Project description:This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes Th1 cell differentiation. P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-polarized CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade in vitro and the consequent inhibition of oxidative phosphorylation, which forces cells to use aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 cell differentiation and suggest that ATP synthase inhibition is a fundamental mechanism by which P2X7 signaling induces the Th1 response.
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