Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 19, Pages E4473-E4482Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1802354115
Keywords
prostate cancer; cell surface antigens; immunotherapy
Categories
Funding
- Prostate Cancer Biorepository Network
- Department of Defense Prostate Cancer Research Program [W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, W81XWH-15-2-0062]
- Lori Milken Prostate Cancer Foundation Young Investigator Award
- Prostate Cancer Foundation Challenge Award
- Department of Defense Prostate Cancer Research Program Physician Research Award [PC160018]
- UCLA Specialized Program of Research Excellence (SPORE) in Prostate Cancer Career Enhancement Award [NIH P50 CA092131]
- STOP CANCER Foundation Seed Grant
- NIH/National Cancer Institute (NCI) Grant [K99 CA218731]
- NIH/NCI Grant [P01 CA168585]
- UCLA SPORE in Prostate Cancer Grant [NIH P50 CA092131, P50 CA092131]
- American Cancer Society [RSG-12-257-01-TBE]
- NCI/NIH Grant [R01 CA220238]
- Gaba Foundation
- UCLA Broad Stem Cell Research Center
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Parker Institute for Cancer Immunotherapy Grant [PICI 20163828]
Ask authors/readers for more resources
Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a transition from an epithelial to a neurosecretory cancer phenotype. Cell surface markers are often associated with specific cell lineages and differentiation states in normal development and cancer. Here, we show that PrAd and NEPC can be broadly discriminated by cell-surface profiles based on the analysis of prostate cancer gene expression datasets. To overcome a dependence on predictions of human cell-surface genes and an assumed correlation between mRNA levels and protein expression, we integrated transcriptomic and cell-surface proteomic data generated from a panel of prostate cancer cell lines to nominate cell-surface markers associated with these cancer subtypes. FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively. Given the lack of effective treatments for NEPC, CEACAM5 appeared to be a promising target for cell-based immunotherapy. As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines. Our findings demonstrate that the surfaceomes of PrAd and NEPC reflect unique cancer differentiation states and broadly represent vulnerabilities amenable to therapeutic targeting.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available