Core2 O-glycan-expressing prostate cancer cells are resistant to NK cell immunity

Abstract

Core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in the O-glycans (core2 O-glycans) of cell surface glycoproteins. We previously revealed that the expression of C2GnT is positively correlated with poor prognosis in prostate cancer patients. However, the detailed mechanisms underlying their poor prognosis remain unclear. In the current study, we report that the core2 O-glycans carried by the surface MUC1 glycoproteins of prostate cancer cells play an important role in the evasion of NK cell immunity. In C2GnT-expressing prostate cancer cells, the MUC1 core2 O-glycans are modified with poly-N-acetyllactosamine. MUC1 glycoproteins carrying poly-N-acetyllactosamine attenuated the interaction of the cancer cells with NK cells, resulting in decreased secretion of granzyme B by the NK cells. Poly-N-acetyllactosamine also interfered with the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to access the cancer cell surface. These effects of poly-N-acetyllactosamine on NK cells render C2GnT-expressing prostate cancer cells resistant to NK cell cytotoxicity. By contrast, C2GnT-deficient prostate cancer cells carrying a lower amount of poly-N-acetyllactosamine than the C2GnT-expressing prostate cancer cells were significantly more susceptible to NK cell cytotoxicity. Our results strongly suggest that C2GnT-expressing prostate cancer cells evade NK cell immunity and survive longer in the host blood circulation, thereby resulting in the promotion of prostate cancer metastasis.

Core 2 β-1, 6-N-acetylglucosaminyltransferase-1 expression in prostate biopsy specimen is an indicator of prostate cancer aggressiveness

“…Our research group has already reported that GCNT1-expressing cancer cells can escape from host immune defense system [15,17]. In this immunological evading 12 mechanism, galectin-3 binding to core 2 branching O-glycans expressed on cancer cell surface is an critical step to interfere contact of host natural killer cells with cancer cells [15,17]. Endogenous galectin-3 expression has been found to correlate with the malignant potential of tumors [28,29,30] and PCa progression [31].…”

“…In our previous study, GCNT1 expressing PCa cells formed poly-N-acetyllactosamine on cell surface [17]. The poly-N-acetyllactosamine is a ligand for galectins [21,22].…”

“…Furthermore, we investigated possible roles of GCNT1 in PCa progression using cell lines which express high or low levels of GCNT1 with in vitro and in vivo experimental systems. knockdown cells (PC-3 cell line) were as previously described [17].…”

Immunosuppressive Functions of Core2 O-Glycans against NK Immunity

“…At present, these novel immunosuppressive functions were demonstrated in bladder cancer (13,23) and prostate cancer (14). However, considering that the correlation of C2GnT expression with a high-metastatic phenotype was observed in several other types of cancers (4-7), it seems plausible that those cancer cells also use these mechanisms.…”

“…This minireview summarizes the newly identified immunosuppressive functions of core2 O-glycans against NK cell immunity with an emphasis on the most recent advances (13,14,23). At present, these novel immunosuppressive functions were demonstrated in bladder cancer (13,23) and prostate cancer (14).…”