Dietary Restriction Enhances CD8 T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 T cell-mediated anti-tumor immunity. DR reshapes CD8 T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth.

An oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.

While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV).

Ketolysis drives CD8 T cell effector function through effects on histone acetylation.

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8 T cell metabolism and effector function. βOHB directly increased CD8 T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge.

Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.

Background: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors.

Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity.

CD8 T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy.

PYGBacking on glycogen metabolism to fuel early memory T cell recall responses.

Zhang et al. (2022) show that TCR signaling promotes the phosphorylation and activation of glycogen phosphorylase B (PYGB) in CD8 memory T (Tmem) cells. PYGB-dependent glycogen mobilization provides a carbon source to support glycolysis and early Tmem cell recall responses.

Fighting in a wasteland: deleterious metabolites and antitumor immunity.

As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture.

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.

CTLA-4 blockade drives loss of T stability in glycolysis-low tumours.

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 cells. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis.

4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses.

Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade.

Asymmetric Wnt Pathway Signaling Facilitates Stem Cell-Like Divisions via the Nonreceptor Tyrosine Kinase FRK-1 in Caenorhabditis elegans.

Asymmetric cell division is critical during development, as it influences processes such as cell fate specification and cell migration. We have characterized FRK-1, a homolog of the mammalian Fer nonreceptor tyrosine kinase, and found it to be required for differentiation and maintenance of epithelial cell types, including the stem cell-like seam cells of the hypodermis. A genomic knockout of frk-1, allele ok760, results in severely uncoordinated larvae that arrest at the L1 stage and have an excess number of lateral hypodermal cells that appear to have lost asymmetry in the stem cell-like divisions of the seam cell lineage.