TY - JOUR
T1 - Immunosuppressive metabolites in tumoral immune evasion
T2 - Redundancies, clinical efforts, and pathways forward
AU - Jennings, Maria Rain
AU - Munn, David
AU - Blazeck, John
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2021.
PY - 2021/10/19
Y1 - 2021/10/19
N2 - 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.
AB - 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.
KW - adenosine
KW - immunotherapy
KW - indoleamine-pyrrole 2,3-dioxygenase
KW - metabolic networks and pathways
KW - tumor escape
UR - http://www.scopus.com/inward/record.url?scp=85118257901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118257901&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-003013
DO - 10.1136/jitc-2021-003013
M3 - Review article
C2 - 34667078
AN - SCOPUS:85118257901
SN - 2051-1426
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 10
M1 - e003013
ER -