Secretory IgA amplification during immune checkpoint blockade enhances the control of tumor growth by enterotropic T cells
The gut microbiota is essential for many aspects of host physiology, and secretory immunoglobulin A (sIgA) modulates its function. The microbiota community determines the efficacy of immune checkpoint blockade (ICB) in cancer immunotherapy; however, mechanisms able to improve this function are not known. Extracellular adenosine triphosphate (ATP) released by the microbiota restricts the sIgA repertoire by limiting T follicular helper (T<sub>FH</sub>) cell activity in the Peyer's patches via stimulation of the ionotropic P2X7 receptor. We show that sIgA amplification by oral administration of the ATP hydrolyzing enzyme apyrase corrects enteropathic features of ICB and improves therapeutic efficacy. Consistent with sIgA function in reshaping the gut ecosystem and enhancing ICB, <i>IgA<sup>-/-</sup></i> mice did not show any improvement of antitumor response by apyrase administration. Mechanistically, data in mice and patients with cancer suggest that invigorated enterotropic cytotoxic T cells expressing the chemokine receptor CCR9 replenish the tumor microenvironment in a CCL25-mediated manner and control tumor growth, resulting in improved ICB efficacy.
Authors
- Andrea Raimondi (ORCID: https://orcid.org/0000-0002-4563-386X)
- Laura Montani (ORCID: https://orcid.org/0000-0002-8243-6734)
- Graziano Pesole (ORCID: https://orcid.org/0000-0003-3663-0859)
- Benedetta De Ponte Conti
- Roshan Singh Thakur (ORCID: https://orcid.org/0000-0001-5284-4975)
- Jens Geginat (ORCID: https://orcid.org/0000-0003-4813-0384)
- Mattia Forcato (ORCID: https://orcid.org/0000-0002-7383-6576)
- Giacomo Mantegazza (ORCID: https://orcid.org/0000-0002-0936-1211)
- Francesco Prisco (ORCID: https://orcid.org/0000-0002-0399-1239)
- Tanja Rezzonico-Jost (ORCID: https://orcid.org/0009-0000-2146-2237)
- Andrea Rinaldi (ORCID: https://orcid.org/0000-0003-3234-0563)
- Grazia Visci (ORCID: https://orcid.org/0000-0003-3238-112X)
- Lisa Perruzza
- Elisabetta Notario
- Silvio Bicciato (ORCID: https://orcid.org/0000-0002-1944-7078)
- Fabio Grassi (ORCID: https://orcid.org/0000-0003-3348-1712)
- Elena Carelli (ORCID: https://orcid.org/0009-0002-5582-9548)
- Matteo Raneri
- Marinella Marzano (ORCID: https://orcid.org/0000-0002-9996-8817)
- Simone G. Moro (ORCID: https://orcid.org/0000-0001-5199-8390)
- Giorgio Gargari (ORCID: https://orcid.org/0000-0001-9077-6328)
- Simone Guglielmetti (ORCID: https://orcid.org/0000-0002-8673-8190)
- Davide Mangani (ORCID: https://orcid.org/0000-0001-5297-0234)
- Samuele Notarbartolo (ORCID: https://orcid.org/0000-0001-5910-4910)
- Frauke Seehusen (ORCID: https://orcid.org/0000-0001-6701-7868)
- Rebecca Marino (ORCID: https://orcid.org/0000-0002-2069-6485)
- Denise Dallavalle
Institutions
- University of Bern (CH)
- Bern University of Applied Sciences (CH)
- University of Padua (IT)
- University of Milan (IT)
- University of Zurich (CH)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Institute of Oncology Research (CH)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- University of Bari Aldo Moro (IT)
- Università della Svizzera italiana (CH)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1126/sciadv.aeb5308
- Citations
- 2
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- National Science Foundation
- Institute for Research in Biomedicine
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Swiss Cancer Research Foundation