Targeting immuno-metabolism to improve anti-cancer therapies

Abstract

The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism. Research over the last decade has revealed that T cell proliferation and differentiation is intimately linked to robust changes in metabolic activity, delineation of which may provide ways to manipulate the immuno-oncologic responses to our advantage. Here, we provide a basic overview of T cell metabolism, discuss what is known about metabolic regulation of T cells during allogeneic HSCT, point to evidence on the importance of T cell metabolism during CAR T cell and solid tumor therapies, and speculate about the role for compounds that might have dual-action on both immune cells and tumor cells simultaneously.

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment

“…Based on recent discoveries in the field of cancer metabolism that we discussed previously, researchers have proposed new rationales behind cancer metabolism, providing insight into why XRT and immune therapy are perhaps the best clinically available weapons we have to fight cancer. Very little effort has been directed toward tackling the metabolic aspect of cancer using radiation and addressing targeting of immune metabolism to improve cancer therapies (77). XRT is the only effective established clinical tool that takes advantage of the metabolic aspect of cancer.…”

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

“…Second- and third-generation CAR-T cells include the expression of costimulatory molecules, such as CD28 or 4–1BB (CD137), which together with the receptor can dramatically improve antitumor activity. The effect of the co-stimulation is not limited to the immune signalling mediated by these co-receptors, but they can also differentially influence cellular metabolism favouring cellular fitness and improve both effector function and persistence of the CAR-T cell (189–192). …”

“…The effect of the costimulation is not limited to the immune signaling mediated by these co-receptors, but they can also differentially influence cellular metabolism favoring cellular fitness and improve both effector function and persistence of the CAR-T cell. [189][190][191][192] In particular, it has been found that co-stimulation through 4-1BB is associated with a longer survival and enhanced memory development when compared to CAR-T cells expressing CD28. 189,192 Interestingly, 4-1BB-expressing cells were also characterized by enhanced mitochondrial biogenesis and metabolism, higher SRC and rates of FAO, as well as a differential expression of metabolic genes favoring FA metabolism over glycolysis, including Cpt1a and Fabp5.…”

“…[189][190][191][192] In particular, it has been found that co-stimulation through 4-1BB is associated with a longer survival and enhanced memory development when compared to CAR-T cells expressing CD28. 189,192 Interestingly, 4-1BB-expressing cells were also characterized by enhanced mitochondrial biogenesis and metabolism, higher SRC and rates of FAO, as well as a differential expression of metabolic genes favoring FA metabolism over glycolysis, including Cpt1a and Fabp5. 191 Signaling through CD28 intracellular domain was also described to increase Cpt1a expression when compared to T cells harboring only the transgenic antigen-specific receptor.…”

Metabolic Pathways in Alloreactive T Cells

“…In some cases, preserved cytotoxicity results from a preservation in cytokine responses in remaining T cells ( 70 ), coupled with a decrease in T cell dysfunction due to lower rates of GVHD ( 97 ). In other cases, better tumor control may result from the dual impact of metabolic modulation on both alloreactive T cells and the underlying malignancy ( 98 , 99 ). It has also been argued that T cell activation, and hence metabolic demands, operate on a continuum, with GVHD-causing T cells at the far end of the activation and metabolic spectrum ( 100 ).…”