Reenergizing T cell anti-tumor immunity by harnessing immunometabolic checkpoints and machineries.

T cells patrol our bodies preventing pathogenic infections and malignant cell outgrowth. However, T cells must be properly controlled because aberrant or persistent T cell responses can damage tissues and contribute to autoimmune diseases and other chronic inflammatory diseases including metabolic syndrome. One regulatory mechanism utilized in immune cells is immunometabolic regulation, which ensures immune cells properly respond to systemic and peripheral metabolic cues. Recent work has suggested that deregulated metabolism in tumor cells creates a microenvironmental barrier for mounting effective anti-tumor immune responses. Here, we discuss how tumor cells evade immunosurveillance by modulating metabolic checkpoints in immune cells and discuss how memory T cells could provide effective anti-tumor responses by sustaining metabolic fitness and longevity

Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane

The PKB (protein kinase B, also called Akt) family of protein kinases plays a key role in insulin signaling, cellular survival, and transformation. PKB is activated by phosphorylation on residues threonine 308, by the protein kinase PDK1, and Serine 473, by a putative serine 473 kinase. Several protein binding partners for PKB have been identified. Here, we describe a protein partner for PKBα termed CTMP, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of PKBα at the plasma membrane. Binding of CTMP reduces the activity of PKBα by inhibiting phosphorylation on serine 473 and threonine 308. Moreover, CTMP expression reverts the phenotype of v-Akt-transformed cells examined under a number of criteria including cell morphology, growth rate, and in vivo tumorigenesis. These findings identify CTMP as a negative regulatory component of the pathway controlling PKB activity

Modulation of caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein

10.1111/j.1462-5822.2012.01824.xCellular Microbiology14101584-1599CEMI

BCL6b mediates the enhanced magnitude of the secondary response of memory CD8 T lymphocytes

A characteristic of the secondary response of CD8 T cells that distinguishes it from the primary response is the generation of greater numbers of effector cells. Because effector CD8 T cells are derived from a pool of less differentiated, replicating cells in secondary lymphoid organs, and because IL-2 mediates effector differentiation, the enhanced secondary response may reflect the enlargement of this generative pool by the transient repression of IL-2-mediated differentiation. We have examined for this function the transcriptional represser BCL6b, a homologue of BCL6 that represses IL-2-induced B cell differentiation. BCL6b is expressed in a small subset of antigen-experienced CD8 T cells. Ectopic expression of BCL6b in CD8 T cells diminishes their growth in response to IL-2 in vitro. Female mice in which the BCL6b gene has been interrupted have normal primary responses of CD8 T cells to infection with vaccinia expressing the H-Y epitope, Uty, but Uty-specific, BCL6b , memory CD8 T cells have diminished recall proliferative responses to this epitope in vitro. BCL6b mice also have normal primary CD8 T cell responses to influenza infection, but nucleoprotein peptide-specific, BCL6b , memory CD8 T cells have a cell autonomous defect in the number of effector cells generated in response to reinfection. Therefore, BCL6b is required for the enhanced magnitude of the secondary response of memory CD8 T cells

Immunoediting instructs tumor metabolic reprogramming to support immune evasion.

Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment

Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8⁺ T cells in tumors.

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 <sup>+</sup> tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 <sup>+</sup> TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 <sup>+</sup> TILs, which also correlated with progressive T cell dysfunction. Cd36 <sup>-/-</sup> T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 <sup>+</sup> TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 <sup>+</sup> T cell dysfunction and serves as a therapeutic avenue for immunotherapies

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity