Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy

• Published in: Biomedicine & pharmacotherapy Vol. 167; p. 115592
• Main Authors: Guil-Luna, Silvia, Rivas-Crespo, Aurora, Navarrete-Sirvent, Carmen, Mantrana, Ana, Pera, Alejandra, Mena-Osuna, Rafael, Toledano-Fonseca, Marta, García-Ortíz, María Victoria, Villar, Carlos, Sánchez-Montero, Maria Teresa, Krueger, Janna, Medina-Fernández, Francisco Javier, De La Haba-Rodríguez, Juan, Gómez-España, Auxiliadora, Aranda, Enrique, Rudd, Christopher E., Rodríguez-Ariza, Antonio
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01-11-2023; Elsevier
• Subjects: Colorectal cancer; GSK-3; Humanized PDXs; PD-L1; Tumor budding; SMIs; IHC; Colorectal cancer; DNTs; GSK-3; GSK-3α; GSK-3β; PI3K; PD-L1; GSK-3i; CTLA-4; PFS; K-M grade; Tumor budding; MSI; NSG; OS; PDX; H&E; Tregs; IP; CMS; ICB; EMT; PBMCs; Humanized PDXs; TB; BD1; BD3; BD2; CRC; TILs; ITBCC; PD-1; TLRs
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115592

Glycogen synthase kinase 3 (GSK-3) has been proposed as a novel cancer target due to its regulating role in both tumor and immune cells. However, the connection between GSK-3 and immunoevasive contexture, including tumor budding (TB) has not been previously examined. Methods: we investigated the expression levels of total GSK-3 as well as its isoforms (GSK-3β and GSK-3α) and examined their potential correlation with TB grade and the programmed cell death-ligand 1 (PD-L1) in colorectal cancer (CRC) tumor samples. Additionally, we compared the efficacy of GSK-3-inhibition with PD-1/PD-L1 blockade in humanized patient-derived (PDXs) xenografts models of high-grade TB CRC.
we show that high-grade (BD3) TB CRC is associated with elevated expression levels of total GSK-3, specifically the GSK-3β isoform, along with increased expression of PD-L1 in tumor cells. Moreover, we define an improved risk stratification of CRC patients based on the presence of GSK-3+/PD-L1+/BD3 tumors, which are associated with a worse prognosis. Significantly, in contrast to the PD-L1/PD-1 blockade approach, the inhibition GSK-3 demonstrated a remarkable enhancement in the antitumor response. This was achieved through the reduction of tumor buds via necrosis and apoptosis pathways, along with a notable increase of activated tumor-infiltrating CD8+ T cells, NK cells, and CD4- CD8- T cells.
our study provides compelling evidence for the clinical significance of GSK-3 expression and TB grade in risk stratification of CRC patients. Moreover, our findings strongly support GSK-3 inhibition as an effective therapy specifically targeting high-grade TB in CRC.
[Display omitted]
•High-grade TB CRC is associated with elevated expression levels of GSK-3 and PD-L1 in tumor cells.•The combination of TB, PD-L1 and GSK-3 expression improves risk stratification of CRC patients.•GSK-3 inhibition as an effective therapy specifically targeting high-grade TB in CRC.