TGM4: An immunogenic prostate-restricted antigen

Zoila A. Lopez-Bujanda, Aleksandar Obradovic, Thomas R. Nirschl, Laura Crowley, Rodney Macedo, Alexandros Papachristodoulou, Timothy O'Donnell, Uri Laserson, Jelani C. Zarif, Ran Reshef, Tiezheng Yuan, Mithil K. Soni, Emmanuel S. Antonarakis, Michael C. Haffner, H. Benjamin Larman, Michael M. Shen, Pawel Muranski, Charles G. Drake

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background Prostate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the Food and Drug Administration-approved vaccine sipuleucel-T, which targets prostatic acid phosphatase (PAP), extends survival for 2-4 months, the identification of new immunogenic tumor-associated antigens (TAAs) continues to be an unmet need. Methods We evaluated the differential expression profile of castration-resistant prostate epithelial cells that give rise to CRPC from mice following an androgen deprivation/repletion cycle. The expression levels of a set of androgen-responsive genes were further evaluated in prostate, brain, colon, liver, lung, skin, kidney, and salivary gland from murine and human databases. The expression of a novel prostate-restricted TAA was then validated by immunostaining of mouse tissues and analyzed in primary tumors across all human cancer types in The Cancer Genome Atlas. Finally, the immunogenicity of this TAA was evaluated in vitro and in vivo using autologous coculture assays with cells from healthy donors as well as by measuring antigen-specific antibodies in sera from patients with prostate cancer (PCa) from a neoadjuvant clinical trial. Results We identified a set of androgen-responsive genes that could serve as potential TAAs for PCa. In particular, we found transglutaminase 4 (Tgm4) to be highly expressed in prostate tumors that originate from luminal epithelial cells and only expressed at low levels in most extraprostatic tissues evaluated. Furthermore, elevated levels of TGM4 expression in primary PCa tumors correlated with unfavorable prognosis in patients. In vitro and in vivo assays confirmed the immunogenicity of TGM4. We found that activated proinflammatory effector memory CD8 and CD4 T cells were expanded by monocyte-derived dendritic cell (moDCs) pulsed with TGM4 to a greater extent than moDCs pulsed with either PAP or prostate-specific antigen (PSA), and T cells primed with TGM4-pulsed moDCs produce functional cytokines following a prime/boost regiment or in vitro stimulation. An IgG antibody response to TGM4 was detected in 30% of vaccinated patients, while fewer than 8% of vaccinated patients developed antibody responses to PSA or prostate-specific membrane antigen (PSMA). Conclusions These results suggest that TGM4 is an immunogenic, prostate-restricted antigen with the potential for further development as an immunotherapy target.

Original languageEnglish (US)
Article numbere001649
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number6
DOIs
StatePublished - Jun 30 2021
Externally publishedYes

Bibliographical note

Funding Information:
Twitter Zoila A Lopez-Bujanda @ZoilaBujanda and Alexandros Papachristodoulou @ Alexandros_P Acknowledgements We thank C Abate-Shen for her assistance in facilitating this collaboration, N Chowdhury, C R Ager, C S Spina, and S L Reiner for discussion and insightful comments, M G Chaimowitz for administrative assistance, and Z J Kerner for his help revising the manuscript. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were in part obtained from the GTEx Portal V7 data repository. The results shown here are in part based on data generated by The Cancer Genome Atlas Research Network (https://www.cancer. gov/tcga) accessed via the R 'recount' package on Bioconductor. Protein expression in human tissues was queried using the Human Protein Atlas repository available online (http://www.proteinatlas.org). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Funding This study was supported by the US National Institutes of Health National Cancer Institute (CA127153 to CD, CA238005 to MMS, and CA237623 to JCZ); the US Department of Defense (W81XWH-13-1-0369); the Patrick C. Walsh Fund; the OneInSix Foundation; the Swiss National Science Foundation (Early Postdoc Mobility Fellowship to AP: P2ZHP3 181557); the National Science Foundation (fellowship to LC: DGE 16-44869); the Prostate Cancer Foundation (PCF Challenge Awards to CGD and MMS, and Young Investigator Awards to HBL and JCZ) and the National Institute of Health Cancer Center Support Grants P30 CA013696 and P30 CA006973).

Publisher Copyright:
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • antigens
  • immunogenicity
  • prostatic neoplasms
  • vaccine

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