Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function

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. MaldonadoJ. Alan Diehl, Vamsi K. Gangaraju, Shikhar Mehrotra

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1969-1990
Number of pages22
JournalCancer Research
Volume82
Issue number10
DOIs
StatePublished - May 15 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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