Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

Regulatory T (T) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function. At the same time, T cells maintain a strong suppression of effector T cells within the TME.

Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia.

Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous.

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.

Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells.

Quantification of Colonic Stem Cell Mutations.

The ability to measure stem cell mutations is a powerful tool to quantify in a critical cell population if, and to what extent, a chemical can induce mutations that potentially lead to cancer. The use of an enzymatic assay to quantify stem cell mutations in the X-linked glucose-6-phosphate dehydrogenase gene has been previously reported.(1) This method requires the preparation of frozen sections and incubation of the sectioned tissue with a reaction mixture that yields a blue color if the cells produce functional glucose-6-phosphate dehydrogenase (G6PD) enzyme.

Colon carcinogenesis in wild type and immune compromised mice after treatment with azoxymethane, and azoxymethane with dextran sodium sulfate.

The association between inflammation and the risk of colorectal cancer (CRC) is well documented in animal models and in humans, but the mechanistic role of inflammation in CRC is less well understood. To address this question, the induction of colon tumors was evaluated in (i) wild type (WT) and athymic BALB/c mice treated with the colon carcinogen azoxymethane (AOM) as a single agent, and (ii) in an inflammation model of colon cancer employing AOM and dextran sodium sulfate (DSS) in WT, athymic, TCRβ(-/-) , TCRδ(-/-) and TCRβ(-/-) TCRδ(-/-) C57Bl/6 mice. The athymic BALB/c mice treated with only AOM developed 90% fewer tumors than the WT mice.

T-cells enhance stem cell mutagenesis in the mouse colon.

A role of inflammation in the etiology of cancer is attributed to the production of reactive oxygen/nitrogen species that can damage DNA. To test this hypothesis, we determined the mutation frequency (MF) in colonic stem cells in C57Bl/6 mice exposed to azoxymethane (AOM), dextran sulfate sodium (DSS) and a combination of AOM and DSS (AOM+DSS). AOM+DSS efficiently and rapidly produces colon tumors in B6 mice.