Secretory IgA amplification during immune checkpoint blockade enhances the control of tumor growth by enterotropic T cells.

DOI
Publisher DOI
PubMed ID
41042869
Abstract
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 (TFH) 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, IgA 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.
Date Issued
2025-10-03
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
De Ponte Conti, Benedetta
Marino, Rebecca
Rezzonico-Jost, Tanja
Forcato, Mattia
Mangani, Davide
Notario, Elisabetta
Gargari, Giorgio
Carelli, Elena
Rinaldi, Andrea
Raimondi, Andrea
Moro, Simone
Marzano, Marinella
Visci, Grazia
Perruzza, Lisa
Raneri, Matteo
Dallavalle, Denise
Mantegazza, Giacomo
Montani, Ludovica
Prisco, Francesco
Takur, Roshan
Geginat, Jens
Seehusen, Frauke
Notarbartolo, Samuele
Pesole, Graziano
Bicciato, Silvio
Guglielmetti, Simone
Grassi, Fabio
Additional Credits
Journal
Science Advances
Publisher
American Association for the Advancement of Science
ISSN
2375-2548
Access(Rights)
open.access
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