Chemotherapy induced immune-modulation via the TXNIP/GDF15 pathway in colorectal cancer

Abstract

Colorectal cancer is the fourth most lethal cancer worldwide. Conventional cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. The evasion of immune cell recognition is a hallmark of cancer, promoting tumour progression. Restoring immune homeostasis in cancer contributes to long-lasting therapeutic success. It is increasingly recognised that chemotherapies, which do not directly target the immune system, can activate immune responses to help promote favourable clinical outcomes. However, the pathways linking chemotherapy with immune modulation of the tumour microenvironment (TME) are poorly understood. Here, in colorectal cancer we identify that Thioredoxin Interacting Protein (TXNIP), a tumour suppressor gene, is induced by chemotherapy by RNA sequencing analysis. Moreover, we find that increased TXNIP, modulated by MondoA, contributes to improved prognosis by regulating the expression and secretion of Growth/ differentiation factor 15 (GDF15). Further experiments show that secreted GDF15 both promotes the differentiation of regulatory T cells (Tregs) and inhibits Natural killer (NK) cells degranulation by binding to CD48, a member of the CD2 subfamily participating in cell activation and differentiation. Accordingly, more analyses on cell lines derived from secondary sites, chemotherapy-resistant models and patient-derived tumour organoids (PDTOs) demonstrate that inactivation of TXNIP/GDF15 axis, and high GDF15 expression, is associated with advanced disease. Collectively, these findings illuminate potentially common pathway whereby chemotherapy-induced cellular stress drives immune remodelling.

Date of Award	1 Apr 2023
Original language	English
Awarding Institution	King's College London
Supervisor	Debashis Sarker (Supervisor) & Tony Ng (Supervisor)