ST6GAL1-mediated sialylation inhibits the antitumor immune response in colorectal cancer.

[PURPOSE] Interferon gamma (IFNG) directly affects the antitumor immune response. ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) is also positively correlated with poor prognosis for colorectal cancer (CRC). we performed some works to exploreexplored the underlying mechanism to further understand immune escape in colorectal cancer (CRC).

[METHODS] First, we used clinical samples to confirm the relationship between ST6GAL1 and CRC. Afterward, we constructed overexpression/knockdown cell lines and performed bulk RNA sequencing, kinase phosphorylation chip, mass spectrometry, and in vitro and in vivo assays to explore the mechanism regulated by ST6GAL1. Finally, we verified the mechanism by performing immunoprecipitation and immunofluorescence (IF) staining.

[RESULTS] ST6-β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) expression was negatively correlated with the response to neoadjuvant chemotherapy in patients with CRC and negatively correlated with the sensitivity to IFNG in CRC cell lines. We confirmed that ST6GAL1 overexpression inhibited the infiltration of effector T cells, the levels of IFNG produced by CD8 T cells and CD4 T cells decreased, and the levels of granzyme B produced by effector cells decreased in animal models. The results of in vitro assays and phosphorylation chip detection revealed that ST6GAL1 inhibited IFNG receptor 1 (IFNGR1) phosphorylation, thus decreasing the activation of the JAK1/STAT1 signaling pathway. Through immunoprecipitation assays and mass spectrometry, we found that ST6GAL1 can sialylate BICD cargo adaptor 2 (BICD2), thereby affecting the interaction between BICD2 and IFNGR1 to ultimately inhibit the phosphorylation of IFNGR1 and promote immune escape.

[CONCLUSIONS] Our results confirmed that ST6GAL1 decreases the sensitivity of tumor cells to IFNG. This study describes a novel mechanism by which ST6GAL1 promotes the immune escape and malignant progression of CRC.