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Inhibiting intracellular CD28 in cancer cells enhances antitumor immunity and overcomes antiPD-1 resistance via targeting PD-L1
Zhen Yang. et al.
Cancer Cell. 2024
This study investigates the role of intracellular CD28 in cancer immune evasion and a new strategy to overcome anti-PD-1 resistance by targeting CD28. The study found that breast cancer cells express intracellular CD28, which promotes PD-L1 expression by binding to and stabilizing CD274 (the gene encoding PD-L1) mRNA, thereby facilitating immune escape. By targeting intracellular CD28 in cancer cells, it is possible to induce tumor-specific CD8+ T cell immunity, suppress tumor growth, and overcome anti-PD-1 resistance. Clinical sample analysis confirmed that high expression of CD28 in cancer cells is associated with elevated PD-L1 expression, reduced CD8+ T cell infiltration, and poor prognosis, suggesting that targeting CD28 in cancer cells could enhance the efficacy of immunotherapy. Moreover, CD28 functions as an RNA-binding protein (RBP) in cancer cells by interacting with SNRPB2 to stabilize CD274 mRNA. SNRPB2 is involved in pre-mRNA splicing and is a key component of the spliceosome. CD28 acts as an adaptor, facilitating the interaction between SNRPB2 and CD274 mRNA, thus maintaining PD-L1 expression. Deleting CD28 reduces PD-L1 expression in cancer cells, inhibits tumor growth, and enhances infiltration of conventional dendritic cells (cDC1) and CD8+ T cells. In particular, the loss of CD28 increases the effector function of CD8+ T cells and reduces exhausted CD8+ T cells, thereby enhancing antitumor immunity. Clinical sample analysis also shows a negative correlation between cancer cell CD28 expression, SNRPB2 expression, and CD8+ T cell infiltration, further confirming the CD28-SNRPB2-PD-L1 axis in cancer cells that suppresses dendritic cell and T cell infiltration and impairs the efficacy of immune checkpoint blockade (ICB). The study suggests that targeting CD28 to reduce PD-L1 expression could be a potential new strategy to enhance immunotherapy and overcome anti-PD-1 resistance. Future research should explore the mechanism of interaction between SNRPB2 and CD274 mRNA and how to target intracellular CD28 in cancer cells without impairing T cell function. Overall, this study reveals the role of intracellular CD28 in promoting PD-L1 expression and immune escape in cancer, providing a new therapeutic strategy targeting CD28 to enhance the efficacy of immunotherapy and overcome anti-PD-1 resistance.
DOI: 10.1016/j.ccell.2024.11.008
02
Jiawei Qiu. et al.
Neuro oncology. 2024
DOI: 10.1093/neuonc/noae268
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