Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed in various solid tumours, and prostaglandin E2 (PGE2) drives the development of malignant tumours. We developed a drug-resistant B16F10 (B16F10-R) tumour mouse model through four rounds of selection in vivo. Subsequently, we investigated changes in PD-L1 expression and lymphocyte infiltration in B16F10-NR and B16F10-R tumours. Additionally, we explored the role of COX2 in acquired resistance to pembrolizumab, an anti-PD-1 treatment. Immune cell infiltration was significantly decreased in resistant tumours compared to B16F10-NR tumours; however, ptgs2 gene expression was significantly elevated in resistant tumours. Aspirin or celecoxib combined with pembrolizumab can effectively reverse tumour drug resistance. In addition, ptgs2 knockout or the use of the EP4 inhibitor E7046 abrogated drug resistance to anti-PD-1 treatment in B16F10-R tumour cells. Our study showed that inhibition of the COX2/PGE2/EP4 axis could increase the number of immune cells infiltrating the tumour microenvironment and recover drug-resistant tumour sensitivity to pembrolizumab. Thus, we highlight COX2 inhibition as a promising therapeutic target for drug-resistant tumours for future consideration.

Adhesive interactions between selectins and their ligands play an essential role during cancer extravasation. Fucosylation of these proteins by fucosyltransferases, or FUTs, is critical for their functions. Using quantitative RT-PCR, we demonstrated that FUT4 and FUT7 are the predominant FUTs expressed in hematopoietic cell line, while FUT3 is heavily expressed by multiple cancer cell lines including the prostate cancer cell line MDA PCa2b. Knockdown of FUT3 expression in MDA PCa2b cells by small interference RNA (siRNA) significantly reduced FUT3 expression. Cell-surface sialyl Lewis antigens were largely abolished. Cell adhesion and cell rolling on the blood vessel wall were simulated by perfusing cancer cells through microtubes coated with recombinant human E-selectin. At physiological levels of wall shear stress, the number of flowing cancer cells recruited to the microtube surface was dramatically reduced by FUT3 knockdown. Higher rolling velocity was also observed, which is consistent with reduced E-selectin binding activity. Interestingly, FUT3 siRNA treatment also significantly reduced the cell growth rate. Combined with the novel siRNA delivery platform recently developed in our laboratory, FUT3 siRNA could be a promising conjunctive therapy aiming at reducing the metastatic virulence of circulating epithelial cancer cells.
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