Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment

Yin, T.; Wang, G.; Ma, Z.; Wang, L.; Chen, R.; Xiang, K.; Tan, L.; Wang, Y.; Chong, M.; Liang, Y.; Pan, C. C.; Alexander, P. B.; Lim, B. J. W.; Wang, E.; Liu, B.; Yan, C.; Li, Q.-J.; Wang, X.-F.

doi:10.1101/2025.02.10.637339

bioRxiv · 10.1101/2025.02.10.637339

Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment

Yin, T.·Wang, G.·Ma, Z.·Wang, L.·Chen, R.·Xiang, K.·Tan, L.·Wang, Y.·Chong, M.·Liang, Y.·Pan, C. C.·Alexander, P. B.·Lim, B. J. W.·Wang, E.·Liu, B.·Yan, C.·Li, Q.-J.·Wang, X.-F.

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Abstract

During initiation and progression, cancerous tissue hijacks a series of elaborate tissue homeostatic mechanisms to avoid immune surveillance, including neuro-immune interactions. Here, we show that amyloid-{beta} precursor protein (APP) and its {beta}-cleavage product amyloid-{beta}1-42 (A{beta}1-42), well-known in the pathogenesis of Alzheimers disease (AD), are expressed in multiple cancer tissues. However, the oncogenic activity of APP is due to its E1 domain, instead of A{beta}1-42. Mechanistically, APP restricts immune cells influx into tumor microenvironment (TME) and impairs CD8+ T cell and NK cell-based immunity, by dampening type I interferon (IFN) response in TME. We also provide proof-of-concept that vaccination targeting APP is effective for cancer prevention. Our current study reveals a previously unrecognized role of APP in cancer immune surveillance, and provides a new strategy for cancer prevention and treatment by targeting APP.

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Yin, T., Wang, G., Ma, Z., Wang, L., Chen, R., Xiang, K., Tan, L., Wang, Y., Chong, M., Liang, Y., Pan, C. C., Alexander, P. B., Lim, B. J. W., Wang, E., Liu, B., Yan, C., Li, Q.-J., Wang, X.-F.. 2025-02-14. Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment. https://doi.org/10.1101/2025.02.10.637339

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