Editors' ChoiceCancer

Cancer catch and sugar release cue immune attack

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Science Translational Medicine  28 Sep 2016:
Vol. 8, Issue 358, pp. 358ec157
DOI: 10.1126/scitranslmed.aai8226

Trastuzumab is an antibody specific to human epidermal growth factor receptor 2 (HER2) that elicits its therapeutic effects in breast cancer by directing antibody-dependent cell-mediated cytotoxicity immune responses against HER2-expressing tumors. Only a minority of patients with HER2-positive disease, specifically those with the highest expression of HER2, is eligible for this treatment, however, and even fewer respond to the single agent alone. Therefore, there is a great need to adapt this therapeutic and broaden the patient population to the greater than 80% of patients with HER2-positive disease who are presently either ineligible or unresponsive to treatment.

A mechanism of immune evasion used by tumors is the modification of the sugar coatings that decorate cancer cells, termed glycocalyx, with sialic acids that suppress numerous pathways of immune activation when they are present in amounts similar to those in healthy tissues. To stimulate activating pathways and limit inhibitory pathways of immune stimulation against HER2-expressing tumors, Xiao et al. designed an antibody-enzyme conjugate to direct the removal of sialic acid sugar residues from HER2-expressing cancer cells. This was achieved by fusing trastuzumab with a sialic acid–cleaving enzyme that ablated the binding of sialic acid–binding immunoglobulin-like lectins, which are ligands with inhibitory immune signaling activities. The treatment also enhanced the binding of an activating natural killer cell receptor to its ligands on breast cancer cell lines. The targeting of a cell surface–modifying enzyme to cancer cells resulted in removal of cell surface sialic acid selectively on HER2-expressing cells. The removal was concentration-dependent, and it enhanced killing of HER2-expressing cells by natural killer immune cells but spared nontargeted cells. Tumor cell killing mediated by the antibody-enzyme conjugate was most dramatically enhanced against breast cancer cells with intermediate or low expression of HER2, as compared with treatment with trastuzumab alone.

This approach demonstrates the potential for antibodies to direct the activity of tethered enzymes to specific cell targets for cell-selective effects. This study also suggests that increasing the susceptibility of tumors to immune cell killing through modification of the glycocalyx on cancer cells may potentiate trastuzumab’s efficacy in the treatment of patients whose tumors have lower expression of HER2.

H. Xiao et al., Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc. Natl. Acad. Sci. U.S.A. 113, 10304–10309 (2016). [Abstract]

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