Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Abstract

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

Dietary restriction of amino acids for Cancer therapy

“…As for AA restrictions in cancer interventions, cumulating research findings of AA restrictions had been discussed, including glycine restriction [6], serine starvation [7][8][9], leucine deprivation [10], glutamine blockade [11,12], asparagine [13] and methionine [14]. NEAA restrictions played limited roles in cancer therapy since there were de novo synthesis pathways, such as glycine [6] and serine [7].…”

“…Leucine deprivation showed mild effects on human breast cancer cells [10], which might due to its exceptional abundance in human proteome. A new derivative of DON, JHU083, blocked glutamine metabolism in TME and induced a metabolic reprogramming of effector T cells relied on acetate to overcome tumor immune evasion [12]. Asparagine restriction could reduce the metastasis of breast cancer without affecting the growth of the primary tumour [13].…”

“…Therefore, it was possible that cancer cells might gain superior capacity to uptake or utilize some AAs compared to the capability of normal cells via multiple signaling pathways, such as GCN2-ATF4 axis [72][73][74][75], or by decreasing AA catabolisms, such as BCAA [76]. Consequently, it should be aware of that the restriction of those AAs might disturb normal cells more than cancer cells, and lead to side effects, such as the application of a glutamine antagonist DON (6diazo-5-oxo-l-norleucine) [11,12]. On the other hand, TME is relatively isolated, so that normal cells, especially immune cells, might have priority to acquire those restricted and limited AAs from the bloodstream, such as lysine.…”

“…Vanderhoof pointed out that "most of the non-energy-related effects of carbohydrates can be related to short-chain fatty acid (SCFA) production". Interesting, in contrast to the inhibition of glutamineutilized metabolism in cancer cells, activated T cells could adapt to glutamine blockade through the upregulation of acetate metabolism to maintain energy (especially ATP) and NADPH homeostasis [12]. The adaptation capability of T cells suggested that SCFAs (including acetate, propionate and butyrate) could be used for maintaining the metabolism of immune cells under AA restriction, and also provided an explanation to the immunomodulatory effects of carbohydrates, especially oligosaccharides and dietary fiber [101,102].…”

“…Due to the demands of cell growth and the needs of newly synthesized proteins as direct effectors of cellular activities, protein biosynthesis is the most energy-demanding process that accounts for~33% of total ATP consumption [3][4][5]. Interestingly, cumulating research findings have demonstrated that amino acid (AA) restrictions play roles in cancer interventions, including glycine restriction [6], serine starvation [7][8][9], leucine deprivation [10], glutamine blockade [11,12], asparagine [13] and methionine [14]. These findings inspire and motivate a number of questions.…”