Radiation therapy induces immunosenescence mediated by p90RSK.

Autor: Imanishi M; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Cheng H; Center for Stem Cell and Regenerative Medicine, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States., Kotla S; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Deswal A; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Le NT; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Chini E; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL, United States., Ko KA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Samanthapudi VSK; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Lee LL; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Herrmann J; Division of Preventive Cardiology, Cardio Oncology Clinic, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States., Xu X; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States., Reyes-Gibby C; Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Yeung SJ; Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Schadler KL; Department of Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Yusuf SW; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Liao Z; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Nurieva R; Division of Basic Science, Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Amir ED; Astrolabe Diagnostics, Inc., Fort Lee, NJ, United States., Burks JK; Division of Center Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Palaskas NL; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Cooke JP; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Lin SH; Department of Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Kobayashi M; Center for Stem Cell and Regenerative Medicine, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States., Yoshimoto M; Center for Stem Cell and Regenerative Medicine, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States., Abe JI; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Jazyk: angličtina
Zdroj: Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2022 Nov 07; Vol. 9, pp. 988713. Date of Electronic Publication: 2022 Nov 07 (Print Publication: 2022).
DOI: 10.3389/fcvm.2022.988713
Abstrakt: Radiation therapy (RT) to the chest increases the patients' risk of cardiovascular disease (CVD). A complete understanding of the mechanisms by which RT induces CVD could lead to specific preventive, therapeutic approaches. It is becoming evident that both genotoxic chemotherapy agents and radiation induce mitochondrial dysfunction and cellular senescence. Notably, one of the common phenotypes observed in cancer survivors is accelerated senescence, and immunosenescence is closely related to both cancer risk and CVD development. Therefore, suppression of immunosenescence can be an ideal target to prevent cancer treatment-induced CVD. However, the mechanism(s) by which cancer treatments induce immunosenescence are incompletely characterized. We isolated peripheral blood mononuclear cells (PBMCs) before and 3 months after RT from 16 thoracic cancer patients. We characterized human immune cell lineages and markers of senescence, DNA damage response (DDR), efferocytosis, and determinants of clonal hematopoiesis of indeterminant potential (CHIP), using mass cytometry (CyTOF). We found that the frequency of the B cell subtype was decreased after RT. Unsupervised clustering of the CyTOF data identified 138 functional subsets of PBMCs. Compared with baseline, RT increased TBX21 (T-bet) expression in the largest B cell subset of Ki67 - /DNMT3a + naïve B cells, and T-bet expression was correlated with phosphorylation of p90RSK expression. CD38 expression was also increased in naïve B cells (CD27 - ) and CD8 + effector memory CD45RA T cells (T EMRA ). In vitro , we found the critical role of p90RSK activation in upregulating (1) CD38 + /T-bet + memory and naïve B, and myeloid cells, (2) senescence-associated β-gal staining, and (3) mitochondrial reactive oxygen species (ROS) after ionizing radiation (IR). These data suggest the crucial role of p90RSK activation in immunosenescence. The critical role of p90RSK activation in immune cells and T-bet induction in upregulating atherosclerosis formation has been reported. Furthermore, T-bet directly binds to the CD38 promoter region and upregulates CD38 expression. Since both T-bet and CD38 play a significant role in the process of immunosenescence, our data provide a cellular and molecular mechanism that links RT-induced p90RSK activation and the immunosenescence with T-bet and CD38 induction observed in thoracic cancer patients treated by RT and suggests that targeting the p90RSK/T-bet/CD38 pathway could play a role in preventing the radiation-associated CVD and improving cancer prognosis by inhibiting immunosenescence.
Competing Interests: Author E-aA was employed by the company Astrolabe Diagnostics, Inc. SL was an Advisory Board member of AstraZeneca, Beyond Spring Pharmaceuticals, STCube Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Imanishi, Cheng, Kotla, Deswal, Le, Chini, Ko, Samanthapudi, Lee, Herrmann, Xu, Reyes-Gibby, Yeung, Schadler, Yusuf, Liao, Nurieva, Amir, Burks, Palaskas, Cooke, Lin, Kobayashi, Yoshimoto and Abe.)
Databáze: MEDLINE
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