Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

Siska, Peter J.; Beckermann, Kathryn E.; Mason, Frank M.; Andrejeva, Gabriela; Greenplate, Allison R.; Sendor, Adam B.; Chiang, Yu‐Chun; Corona, Armando L.; Gemta, Lelisa; Vincent, Benjamin G.; Wang, Richard C.; Kim, Bumki; Hong, Jiyong; Chen, Chiu Lan; Bullock, Timothy N. J.; Irish, Jonathan M.; Rathmell, W. Kimryn; Rathmell, Jeffrey C.

doi:10.1172/jci.insight.93411

Cited by 276 publications

(219 citation statements)

References 65 publications

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“…We controlled the specificities of mitochondrial stains (Figure 2C) and confirmed that changes in MMP and MROS levels are not due to cell size differences (Figure 2D). Electron microscopy shows that mitochondria within CD44 + CD8 + TILs from advanced tumors lose the typical rod-like structure as described (Siska et al, 2017). They display poorly defined membranes and cristae compared to those in splenic T cells (Figure 2E), confirming that CD8 + TILs experience mitochondrial stress within growing tumors.…”

Section: Resultssupporting

confidence: 56%

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

et al. 2017

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Summary How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8+ TILs enhance PPAR-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8+ TILs’ effector functions although co-inhibitor expression increases during tumor progression regardless of their antigen specificity. Further promoting FA catabolism improves the CD8+ TIL’s ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.

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Section: Resultssupporting

confidence: 56%

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

et al. 2017

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“…Flow cytometry is a high‐throughput method of studying T cells, and MitoTracker® dyes can be combined with fluorescent antibodies to yield a detailed phenotypic profile of cell populations of interest. This approach has been used to study T cell mitochondria in animal models, and in human studies of diseases such as cancer, HIV, and HBV infection . However, for data to be comparable between independent experiments, care must be taken to ensure the consistency of the fluorescent signal.…”

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confidence: 99%

A Reproducible, Objective Method Using MitoTracker® Fluorescent Dyes to Assess Mitochondrial Mass in T Cells by Flow Cytometry

et al. 2018

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MitoTracker ® dyes are fluorescent compounds that allow cellular mitochondrial content to be measured semi‐quantitatively by flow cytometry and have been used extensively in immunology publications. However, the parameters commonly reported, mean or median fluorescence intensity and percentage of cells that are MitoTracker® “high”, can be influenced by variability in cytometer setup, dye stability, and operator subjectivity, making it difficult to compare data between experiments. Here, we describe a method to identify MitoTracker® “high” populations in an objective manner. When analyzing data, we first removed outliers using a pre‐specified threshold, determined the fluorescence intensity of the brightest and dimmest events to obtain the fluorescence range and then gated cells within the top 90% of this range. This strategy substantially reduced variability between technical replicates and produced consistent results when data were analyzed by different operators. Consistent with previous reports and other analysis strategies, this analysis method demonstrated that within an individual, CD4+ T cells exhibit significantly higher mitochondrial mass than CD8+ T cells. Objective gating increases the reliability and utility of data generated using MitoTracker® dyes. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

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“…Exhausted T cells in models of cancer or chronic virus infection often have defects in mitochondria number, size, and voltage potential and function (Bengsch et al, 2016; Scharping et al, 2016; Siska et al, 2017). One study has proposed that the tumor microenvironment downregulates mitochondrial biosynthesis by inhibiting expression of PPAR-gamma coactivator 1α (PGC1α), while another has suggested ROS induced damage may induce decreased mitochondrial mass (Scharping et al, 2016; Siska et al, 2017). Scharping et al has successfully demonstrated that overexpression of PGC1α in tumor-specific T cells is able to prevent downregulation of mitochondrial mass and enhance T cell functionality in the tumor microenvironment.…”

Section: Challenges T Cells Face In the Solid Tumor Microenvironmentmentioning

confidence: 99%

Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition

Ecker

Riley

2018

Cell Metabolism

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Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

Cited by 276 publications

References 65 publications

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

A Reproducible, Objective Method Using MitoTracker® Fluorescent Dyes to Assess Mitochondrial Mass in T Cells by Flow Cytometry

Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition

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