학술논문
A tumor-restricted glycoform of podocalyxin is a highly selective marker of immunologically cold high-grade serous ovarian carcinoma.
Document Type
Academic Journal
Author
Brassard J; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Hughes MR; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Dean P; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.; Hernaez DC; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Thornton S; Molecular and Advanced Pathology Core (MAPcore), University of British Columbia, Vancouver, BC, Canada.; Banville AC; British Columbia Cancer Agency, Victoria, BC, Canada.; Smazynski J; British Columbia Cancer Agency, Victoria, BC, Canada.; Warren M; British Columbia Cancer Agency, Victoria, BC, Canada.; Zhang K; British Columbia Cancer Agency, Victoria, BC, Canada.; Milne K; British Columbia Cancer Agency, Victoria, BC, Canada.; Gilks CB; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.; Mes-Masson AM; Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada.; Huntsman DG; Molecular and Advanced Pathology Core (MAPcore), University of British Columbia, Vancouver, BC, Canada.; Department of Molecular Oncology, University of British Columbia, Vancouver, BC, Canada.; Nelson BH; British Columbia Cancer Agency, Victoria, BC, Canada.; Roskelley CD; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.; McNagny KM; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101568867 Publication Model: eCollection Cited Medium: Print ISSN: 2234-943X (Print) Linking ISSN: 2234943X NLM ISO Abbreviation: Front Oncol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2234-943X
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.
Competing Interests: Authors MH, PD, KM and CR hold patents for the PODXL antibodies described in this manuscript including issued US Patents US11090383B2, US11390673B2. KM and CR hold a patent claiming methods for detecting and treating cancer related to podocalyxin US9309323B2. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Brassard, Hughes, Dean, Hernaez, Thornton, Banville, Smazynski, Warren, Zhang, Milne, Gilks, Mes-Masson, Huntsman, Nelson, Roskelley and McNagny.)
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
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.
Competing Interests: Authors MH, PD, KM and CR hold patents for the PODXL antibodies described in this manuscript including issued US Patents US11090383B2, US11390673B2. KM and CR hold a patent claiming methods for detecting and treating cancer related to podocalyxin US9309323B2. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Brassard, Hughes, Dean, Hernaez, Thornton, Banville, Smazynski, Warren, Zhang, Milne, Gilks, Mes-Masson, Huntsman, Nelson, Roskelley and McNagny.)