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Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8 + T cells via ME1 up-regulation.

Authors :
Gicobi JK
Mao Z
DeFranco G
Hirdler JB
Li Y
Vianzon VV
Dellacecca ER
Hsu MA
Barham W
Yan Y
Mansfield AS
Lin Y
Wu X
Hitosugi T
Owen D
Grams MP
Orme JJ
Lucien F
Zeng H
Park SS
Dong H
Source :
Science advances [Sci Adv] 2023 Nov 17; Vol. 9 (46), pp. eadi2414. Date of Electronic Publication: 2023 Nov 15.
Publication Year :
2023

Abstract

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8 <superscript>+</superscript> T cells. We have termed the rebound of cytotoxic CD8 <superscript>+</superscript> T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1 <superscript>+</superscript> CD8 <superscript>+</superscript> T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8 <superscript>+</superscript> T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Details

Language :
English
ISSN :
2375-2548
Volume :
9
Issue :
46
Database :
MEDLINE
Journal :
Science advances
Publication Type :
Academic Journal
Accession number :
37967193
Full Text :
https://doi.org/10.1126/sciadv.adi2414