Abstract |
Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. SIGNIFICANCE: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.
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Authors | Paramita Chakraborty, Rasesh Y Parikh, Seungho Choi, Danh Tran, Monika Gooz, Zachariah T Hedley, Do-Sung Kim, Dariusz Pytel, Inhong Kang, Satish N Nadig, Gyda C Beeson, Lauren Ball, Meenal Mehrotra, Hongjun Wang, Stefano Berto, Viswanathan Palanisamy, Hong Li, Shilpak Chatterjee, Paulo C Rodriguez, Eduardo N Maldonado, J Alan Diehl, Vamsi K Gangaraju, Shikhar Mehrotra |
Journal | Cancer research
(Cancer Res)
Vol. 82
Issue 10
Pg. 1969-1990
(05 16 2022)
ISSN: 1538-7445 [Electronic] United States |
PMID | 35404405
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
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Copyright | ©2022 American Association for Cancer Research. |
Chemical References |
- Carbon Monoxide
- eIF-2 Kinase
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Topics |
- Apoptosis
- Autophagy
- Carbon Monoxide
(pharmacology)
- Endoplasmic Reticulum Stress
(physiology)
- Humans
- T-Lymphocytes
(metabolism)
- eIF-2 Kinase
(genetics, metabolism)
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