Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

Abstract

Tumors accumulate metabolites that deactivate infiltrating immune cells and polarize them toward anti-inflammatory phenotypes. We provide a comprehensive review of the complex networks orchestrated by several of the most potent immunosuppressive metabolites, highlighting the impact of adenosine, kynurenines, prostaglandin E2, and norepinephrine and epinephrine, while discussing completed and ongoing clinical efforts to curtail their impact. Retrospective analyses of clinical data have elucidated that their activity is negatively associated with prognosis in diverse cancer indications, though there is a current paucity of approved therapies that disrupt their synthesis or downstream signaling axes. We hypothesize that prior lukewarm results may be attributed to redundancies in each metabolites’ synthesis or signaling pathway and highlight routes for how therapeutic development and patient stratification might proceed in the future.

Dysregulated metabolites and lipids in serum of patients with acute hepatitis E: A longitudinal study

“…Adenosine (increased), kynurenate and PGD2 (decreased) are known to be immunosuppressive; hence, the differential expressions in these metabolites may suggest differential modulation of immunosuppressive processes in the HEV group. Interestingly, the biosynthetic pathways for generating these immunosuppressive metabolites are redundant and known to coordinate and stimulate each other 32 . Pantothenate (increased in the HEV group) is an essential precursor for the biosynthesis of coenzyme A, which plays a crucial role in carbohydrate, lipid and amino acid metabolism 33 .…”

Luteolin Potentially Treating Prostate Cancer and COVID-19 Analyzed by the Bioinformatics Approach: Clinical Findings and Drug Targets

“…Statistical analysis data indicate that non-infectious conditions, such as diabetes and cancers, have numerous cases worldwide (30). Among cancer cases, the tumor microenvironment may be altered via depositing metabolites as a result of reduced immunity (31), possibly causing increased risk of infections including SARS-CoV-2 (32). It is presently reported that the COVID-19 pandemic and uncertain SARS-CoV-2 variants are still persisting and evolving diffusely.…”

Innate antiviral immunity: how prior exposures can guide future responses

“…Tryptophan metabolites are another class of metabolites that can regulate antiviral IFNs in humans and mice. The degradation of tryptophan to its byproductsincluding kynureninehas been generally associated with tumor tolerance and immune dysfunction in several chronic viral infections (including HIV-1) in humans [41,42]. Moreover, tryptophan metabolites have been ascribed a putative neuroprotective role and might suppress inflammation in the central nervous system (CNS) during multiple sclerosis in vivo in mouse models and in humans, although this warrants further investigation [43,44].…”