CD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs
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s41467-024-45625-0.pdf
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Published version
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3.31 MB
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Author(s)
Palmeri, Joseph R
Lax, Brianna M
Peters, Joshua M
Duhamel, Lauren
Stinson, Jordan A
Santollani, Luciano
Lutz, Emi A
Pinney, William
Bryson, Bryan D
Dane Wittrup, K
Date Issued
March 1, 2024
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Palmeri, J.R., Lax, B.M., Peters, J.M. et al. CD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs. Nat Commun 15, 1900 (2024).
Version
Final published version
Abstract
Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Ragon Institute of MGH, MIT and Harvard
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DOI of Published Version
10.1038/s41467-024-45625-0
