Journal Article

Immunotherapeutic approach to reduce senescent cells and alleviate senescence‐associated secretory phenotype in mice

Foltz, Jennifer A., Kanakaraj, Leah, Wang, Zheng, Zhu, Xiaoyun, Encalada, Nicole, Wang, Meng, You, Lijing, Foster, Mark, Marsala, Lynne, Dee, Michael J., Shrestha, Niraj, Chaturvedi, Pallavi, Liu, Bai, Fang, Byron, Valdivieso, Nicole, Cubitt, Celia C., Egan, Jack O., Jeng, Emily K., Tran, Jennifer, Muniz, Gabriela J., Schappe, Timothy, Echeverri, Christian, Carvalho, Ana, Wong, Pamela, Spanoudis, Catherine, Fehniger, Todd A., Gilkes, Crystal, George, Varghese, Leclerc, Gilles M., Jiao, Jin‐an, Rhode, Peter R., Kong, Lin, Janney, Christopher, Li, Liying, Deth, Richard, Berrien‐Elliott, Melissa M., Wong, Hing C., Hsiao, Karin

2023

Overview

Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro‐inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single‐nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell‐cycle, and senescence‐associated pathways in naturally aged mice. Long‐term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence‐associated diseases. Bifunctional immunotherapeutic HCW9218 functions as a novel SNC‐reducing and senomorphic agent in mice. Subcutaneous administration of HCW9218 activates NK, innate lymphoid group‐1, and CD8+ T cells, and neutralizes TGF‐ß to reduce senescent cells (SNC‐reducing) and SASP (senomorphic) leading to lower chronic inflammation and restored tissue homeostasis.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Acidification / Aging / Animals / Antigens / Beta cells / Cells / cellular immunology / Cellular Senescence - genetics / circadian genes / Circadian rhythms / Cyclin-dependent kinases / Diabetes / Diabetes mellitus / Experiments / Fibrosis / Flow cytometry / Gene expression / Genotype & phenotype / Glucose tolerance / Growth factors / Homeostasis / Immune system / Immunological tolerance / Immunotherapy / Inflammation / Insulin resistance / Kinases / Lymphocytes / Memory / Metabolism / Mice / Pancreas / Phenotype / Phenotypes / physical performance / Senescence / Senescence-Associated Secretory Phenotype / senescent cell reduction / senomorphic / Sequence analysis / Transcriptomics / Transforming growth factor-b / type 2 diabetes