A systematic screen surfaces transglutaminase 4 as a tissue-restricted prostate antigen with stronger T-cell and antibody responses than PAP or PSA.
Journal for ImmunoTherapy of Cancer · June 30, 2021 · DOI: 10.1136/jitc-2020-001649
Lopez-Bujanda ZA, Obradovic A, Nirschl TR, et al. TGM4: an immunogenic prostate-restricted antigen. J Immunother Cancer. 2021;9(6):e001649. doi:10.1136/jitc-2020-001649
Lopez-Bujanda, Z. A., Obradovic, A., Nirschl, T. R., Crowley, L., Macedo, R., Papachristodoulou, A., O’Donnell, T., Laserson, U., Zarif, J. C., Reshef, R., Yuan, T., Soni, M. K., Antonarakis, E. S., Haffner, M. C., Larman, H. B., Shen, M. M., Muranski, P., & Drake, C. G. (2021). TGM4: an immunogenic prostate-restricted antigen. Journal for ImmunoTherapy of Cancer, 9(6), e001649. https://doi.org/10.1136/jitc-2020-001649
@article{lopezbujanda2021tgm4,
title = {{TGM4}: an immunogenic prostate-restricted antigen},
author = {Lopez-Bujanda, Zoila A and Obradovic, Aleksandar and Nirschl, Thomas R and Crowley, Laura and Macedo, Rodney and Papachristodoulou, Alexandros and O'Donnell, Timothy and Laserson, Uri and Zarif, Jelani C and Reshef, Ran and Yuan, Tiezheng and Soni, Mithil K and Antonarakis, Emmanuel S and Haffner, Michael C and Larman, H Benjamin and Shen, Michael M and Muranski, Pawel and Drake, Charles G},
journal = {Journal for ImmunoTherapy of Cancer},
volume = {9},
number = {6},
pages = {e001649},
year = {2021},
doi = {10.1136/jitc-2020-001649}
}
Transglutaminase 4 (TGM4) is a prostate-restricted, androgen-responsive protein that the authors identify as a high-immunogenicity tumor-associated antigen for castration-resistant prostate cancer. In autologous co-culture assays and in patient sera from a neoadjuvant clinical trial, TGM4 elicited stronger CD8 and CD4 T-cell expansion than prostatic acid phosphatase (PAP) or prostate-specific antigen (PSA), and 30% of vaccinated patients developed IgG antibodies against TGM4 — versus fewer than 8% for PSA or PSMA. The candidate emerged from a systematic differential-expression screen across mouse castration-resistant prostate epithelial cells, tissue atlases, and TCGA tumor types, and elevated TGM4 expression in primary tumors correlated with unfavorable prognosis.
In this publication:
Most metastatic castration-resistant prostate cancer (CRPC) patients eventually exhaust hormone-deprivation therapies, and the only FDA-approved cellular vaccine for prostate cancer — sipuleucel-T, which targets prostatic acid phosphatase (PAP) — extends survival by just 2–4 months. The bottleneck is a shortage of prostate-restricted antigens that the immune system can actually mount a strong response against.
To find new candidates, the authors first looked at which genes go up in mouse castration-resistant prostate epithelial cells after a cycle of androgen withdrawal and replacement, then filtered for genes whose expression was largely restricted to the prostate across mouse and human tissue atlases, and finally checked their expression across all tumor types in The Cancer Genome Atlas. Transglutaminase 4 (TGM4) emerged as the strongest candidate: highly expressed in luminal-origin prostate tumors, low in most other tissues, and associated with worse prognosis when elevated in primary tumors.
They then tested whether TGM4 could provoke a real immune response. Monocyte-derived dendritic cells loaded with TGM4 expanded effector-memory CD8 and CD4 T cells from healthy donors more strongly than the same dendritic cells loaded with PAP or prostate-specific antigen (PSA). T cells primed with TGM4-loaded dendritic cells produced functional cytokines after a prime-boost regimen. Most striking, in sera from prostate cancer patients enrolled in a neoadjuvant clinical trial, 30% of vaccinated patients had developed IgG antibodies against TGM4 — compared with under 8% for PSA or PSMA — confirming that TGM4 is naturally immunogenic in humans, not just in vitro.
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