PTX3 induces the expression of PD-L1 and promotes breast cancer immune escape.

BACKGROUND

Pentraxin 3 (PTX3) is an inflammatory mediator involved in tumorigenesis; however, its role in tumor immune evasion remains elusive. Herein, we demonstrate that PTX3 promotes immune evasion in breast cancer by upregulating PD-L1.

METHODS

RT-qPCR and Western blot were performed to assess PD-L1 expression in human and murine breast cancer cells. Cell surface PD-L1 was assayed by flow cytometry. Small interfering RNA and CRISPR-Cas9 were used to inhibit PTX3 expression. Co-culture experiments were conducted to evaluate the suppressive effects of tumor cells on CD8 + T cell activation. An immunocompetent BALB/c mouse allograft model was utilized, and tumor-infiltrating CD8 + T cells were analyzed by flow cytometry and immunohistochemistry.

RESULTS

PTX3 enhanced PD-L1 protein levels through the inhibition of autophagy. PTX3 increased the expression of the E3 ligase RNF216 and caused Beclin-1 degradation, which suppressed autophagy, thereby preventing autophagy-mediated PD-L1 degradation. Co-culture experiments demonstrate that PTX3-overexpressing breast cancer cells suppressed CD8 + T cell function, as evidenced by reduced production of IFN-γ and Granzyme B, whereas PTX3-depleted cells had the opposite effects. In vivo allograft studies revealed that depletion of PTX3 reduced PD-L1 expression, enhanced CD8 + T cell infiltration, and inhibited tumor growth in immunocompetent mice.

CONCLUSION

PTX3 promotes PD-L1 expression and immune evasion in breast cancer. Therefore, targeting PTX3 may represent a potential therapeutic strategy to counteract this immune escape.