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  • In contrast with hydrophilic metabolites the lipid profile w

    2018-10-25

    In contrast with hydrophilic metabolites, the lipid profile was relatively uniform among samples and did not highlight their heterogeneity. The levels CEs with long-chain highly desaturated fatty acids were elevated in tumors; this was consistent with the notion that clear cell RCCs are rich in CEs and TGs (Gebhard et al., 1987; Drabkin and Gemmill, 2012; Saito et al., 2016). Interestingly, our lipidomics platform identified rare lipid species that were specific to tumor tissues and that have not been reported before; these were typically CEs with very long chains or TGs with ether links. Although the function of these lipid molecules remains to be elucidated, they have the potential to be exploited as biomarkers for diagnosis or drug targeting. Our metabolic analysis of kidney cancer samples revealed the existence of intratumor metabolic heterogeneity. The results led to the identification of pyruvate metabolism as a vulnerability of kidney cancer. Hensley et al. most recently showed metabolic heterogeneity by preoperative multimodality imaging combined with intraoperative 13C glucose in human lung cancer, and tied this heterogeneity to differences in PDH flux (Hensley et al., 2016). We must continue to identify exploitable vulnerabilities by further studying metabolic features of cancer in patients.
    Funding Source This work was wholly supported by Takeda Pharmaceutical Company Limited.
    Conflicts of Interest
    Author Contributions
    Acknowledgments
    Introduction CD8+ T bcr-abl inhibitor respond to pathogens and tumors following T cell receptor (TCR) recognition of specific peptides presented by the major histocompatibility complex (MHC). TCR-activated cells secrete interleukin 2 (IL-2), which promotes expression of CD25, the IL-2 receptor α chain that forms the high-affinity IL-2 receptor (IL2-R) together with the constitutively expressed β (CD122) and common γ chains (γc; CD132). Antigen recognition by the TCR thus ensures IL-2-dependent clonal expansion of cytotoxic T cell populations (Cantrell and Smith, 1984). Following their expansion and differentiation phase, most antigen-specific effector T cells die, and the few surviving cells develop into memory T cells. At this stage, memory cells depend largely on IL-15 (Schluns et al., 2002; Becker et al., 2002; Goldrath et al., 2002), a cytokine that shares CD122 and CD132 chains with IL-2 (Grabstein et al., 1994). CD8+ memory T cells, characterized by a CD44hiCD122hi phenotype, respond more rapidly to antigen and produce larger amounts of cytokines after antigenic challenge. In addition to conventional memory CD8+ T cells, experimental evidence has identified a preexisting pool of CD8+ T cells with a CD44hiCD122hi phenotype (Dubois et al., 2006). This population is found at high frequency in mice with impaired differentiation of conventional CD44loCD122lo CD8+ T cells, suggesting a distinct origin (Atherly et al., 2006; Broussard et al., 2006). Non-conventional CD44hiCD122hi CD8+ T cells need IL-15 to expand (Dubois et al., 2006) and are absent in IL-15−/− mice (Judge et al., 2002). They express NK (natural killer) receptors such as NKG2D, NKG2A/C/E, CD94 and Ly46, which recognize NK ligands in an MHC class I context (Dubois et al., 2006). Cytokine-mediated expansion of memory-like CD8+ T cells provides them with innate-like (non-antigen-dependent) abilities for target recognition and concurs with the capacity of IL-2 or IL-15 to generate potent CD8+ T cell-dependent anti-tumor responses (Murphy et al., 2003). Diacylglycerol kinases (DGK) α and ζ are lipid kinases that limit diacylglycerol (DAG)-dependent activation pathways downstream of the TCR (Merida et al., 2015). Their upregulation in tumor infiltrating lymphocytes (TIL) has been linked to generation of hyporesponsive states that contribute to immune evasion by tumors (Riese et al., 2013). DGKζ-deficient mice show stronger anti-tumor effects in antigen-dependent models, and mouse models of chimeric antigen receptor-engineered (CAR). T cell-infiltrating solid tumors show high expression of both DGK isoforms (Riese et al., 2011; Riese et al., 2013). DGKζ-deficient mice have greater numbers of CD44hiCD122hi CD8+ T cells (Riese et al., 2011) and DGKζ deficiency enhances homeostatic expansion of CD8+ T cells in lymphopenic hosts (Zhong et al., 2003). Whether this is the result of an intrinsic advantage in response to cytokines caused by selective DGKζ deficiency has not been addressed.