A tumor-restricted glycoepitope of podocalyxin correlates with immune evasion in high-grade serous ovarian carcinoma.

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) is an aggressive tumor with a 5-year disease-free survival of roughly 15%, partly because it is usually diagnosed at an advanced stage. Podocalyxin (Podxl) is a highly glycosylated sialomucin normally expressed by vascular endothelia and kidney podocytes. Strikingly, Podxl expression is frequently upregulated by a variety of tumors (including HGSOC) and is consistently associated with poor prognosis. We capitalized on the fact that glycosylation pathways are frequently dysregulated in cancer to develop an antibody, PODO447, that recognizes a tumor-restricted glycoform of Podxl not expressed on normal tissue. While the exact epitope remains to be identified, our results suggest that PODO447 binds an epitope comprising a peptide domain of Podxl in combination with the core 1 O-GalNAc glycan (T-antigen). When coupled to a cytotoxin, a PODO447-antibody-drug conjugate (ADC) effectively kills human tumor cells in vitro and in xenografted mice. While the vast majority of ovarian tumors highly express the Podxl core protein, only a subset of these express the PODO447 epitope. Strikingly, tumors that express a high level of PODO447 epitope tend to be those that lack infiltrating CD8+ T cells and CD20+ B cells: a phenotype that has previously been linked to immune evasion and poorest disease-free survival. Furthermore, we find that PODO447 is a more consistent marker of these immunologically “cold” tumors than a number of other markers, including CA125, mesothelin and folate receptor α. These results highlight the PODO447-epitope as a highly selective diagnostic marker of poor outcome tumors and the PODO447-ADC as a novel strategy for therapeutic intervention. This research was supported by the Canadian Institutes of Health Research (Grant Number: PJT-166180), the School of Biomedical Engineering (The University of British Columbia) postdoctoral fellowship and the Michael Smith Foundation for Health Research (MSFHR) research trainee award.