A tumor-restricted glycoform of podocalyxin is a highly selective marker of immunologically cold high-grade serous ovarian carcinoma

Julyanne Brassard; Michael R Hughes; Pamela Dean; Diana Canals Hernaez; Shelby Thornton; Allyson C Banville; Julian Smazynski; Mary Warren; Kevin Zhang; Katy Milne; C Blake Gilks; Anne-Marie Mes-Masson; David G Huntsman; Brad H Nelson; Calvin D Roskelley; Kelly M McNagny

doi:10.3389/fonc.2023.1286754

A tumor-restricted glycoform of podocalyxin is a highly selective marker of immunologically cold high-grade serous ovarian carcinoma

Front Oncol. 2023 Dec 21:13:1286754. doi: 10.3389/fonc.2023.1286754. eCollection 2023.

Authors

Julyanne Brassard¹, Michael R Hughes¹, Pamela Dean², Diana Canals Hernaez¹, Shelby Thornton³, Allyson C Banville⁴, Julian Smazynski⁴, Mary Warren⁴, Kevin Zhang⁴, Katy Milne⁴, C Blake Gilks⁵, Anne-Marie Mes-Masson⁶, David G Huntsman^{3

7}, Brad H Nelson⁴, Calvin D Roskelley², Kelly M McNagny¹

Affiliations

¹ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
² Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
³ Molecular and Advanced Pathology Core (MAPcore), University of British Columbia, Vancouver, BC, Canada.
⁴ British Columbia Cancer Agency, Victoria, BC, Canada.
⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁶ Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada.
⁷ Department of Molecular Oncology, University of British Columbia, Vancouver, BC, Canada.

Abstract

Introduction: Targeted-immunotherapies such as antibody-drug conjugates (ADC), chimeric antigen receptor (CAR) T cells or bispecific T-cell engagers (eg, BiTE^®) all aim to improve cancer treatment by directly targeting cancer cells while sparing healthy tissues. Success of these therapies requires tumor antigens that are abundantly expressed and, ideally, tumor specific. The CD34-related stem cell sialomucin, podocalyxin (PODXL), is a promising target as it is overexpressed on a variety of tumor types and its expression is consistently linked to poor prognosis. However, PODXL is also expressed in healthy tissues including kidney podocytes and endothelia. To circumvent this potential pitfall, we developed an antibody, named PODO447, that selectively targets a tumor-associated glycoform of PODXL. This tumor glycoepitope is expressed by 65% of high-grade serous ovarian carcinoma (HGSOC) tumors.

Methods: In this study we characterize these PODO447-expressing tumors as a distinct subset of HGSOC using four different patient cohorts that include pre-chemotherapy, post-neoadjuvant chemotherapy (NACT) and relapsing tumors as well as tumors from various peritoneal locations.

Results: We find that the PODO447 epitope expression is similar across tumor locations and negligibly impacted by chemotherapy. Invariably, tumors with high levels of the PODO447 epitope lack infiltrating CD8⁺ T cells and CD20⁺ B cells/plasma cells, an immune phenotype consistently associated with poor outcome.

Discussion: We conclude that the PODO447 glycoepitope is an excellent biomarker of immune "cold" tumors and a candidate for the development of targeted-therapies for these hard-to-treat cancers.

Keywords: glycoepitope; high-grade serous ovarian carcinoma; immune cold; immunotherapy; podocalyxin.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Canadian Institutes of Health Research (PJT-166180), by a Terry Fox New Frontiers Program Project Grant and by a Canadian Cancer Society Innovation Project Grant. JB was supported by a Research Trainee Award from the Michael Smith Foundation for Health Research.