Associate Professor Yong Loo Lin School of Medicine, NUS Singapore, Singapore
Disclosure(s):
Yongliang Zhang, PhD: No financial relationships to disclose
Introduction/Rationale: CD8+ T cells play a central role in anti-tumor immunity and are primary targets of tumor immune evasion strategies. Their activation, proliferation and cytotoxic effector functions are tightly regulated by intracellular signaling molecules. Dual-specificity phosphatases (DUSPs) are key signaling regulators that dephosphorylate both serine/threonine and tyrosine residues in their substrates, thereby modulating various cellular processes involved in both cancer development and anti-tumor immunity. DUSP4 is one of the DUSPs whose role in tumor development and anti-tumor immunity remains poorly understood.
Methods: Wildtype (WT) and DUSP4 knockout (KO) mice were treated with AOM/DSS to induce colorectal tumours to investigate the role of DUSP4 in colorectal cancer (CRC). Naive CD4+ and CD8+ T cells were isolated from WT and DUSP4 KO mice to investigate the function of DUSP4 in regulation of T cell activation, differentiation, and effector function. Expression of DUSP4 in CRC patient samples was determined to analyze its association with patient survival.
Results: DUSP4 KO exhibit increased colonic tumorigenesis following AOM/DSS treatment. In addition, CRC patients with low DUSP4 expression exhibited significantly lower survival compared to those with high DUSP4. Interestingly, DUSP4 expression in tumor cells did not influence their growth. Instead, the increased tumor development in the KO mice was attributed to a compromised anti-tumor immune response. Further analysis revealed that DUSP4-deficient CD8+ T cells exhibited reduced activation, proliferation and effector function compared to WT cells, associated with increased ERK activation. Moreover, these cells showed elevated exhaustion phenotypes, which can be reversed by inhibition of ERK.
Conclusion: These findings demonstrate that DUSP4 supports CD8+ T cell-mediated anti-tumor immunity, likely through modulation of ERK activation, and suggest that DUSP4 may serve as a promising therapeutic target for enhancing anti-tumor immune responses.
