Secretory IgA prevents small intestinal alterations in cancer immunotherapy and enhances control of tumor growth by enterotropic T cells . PacBio sequencing

The gut microbiota is essential for many aspects of host physiology, and locally generated secretory IgA (SIgA) modulates its function. Microbiota community determines the efficacy of immune checkpoint blockade (ICB) in cancer immunotherapy. Extracellular ATP (eATP) released by the microbiota restricts the SIgA repertoire by limiting T follicular helper (Tfh) cells activity in the Peyer's Patches (PPs) via stimulation of ionotropic P2X7 receptor. Here we show that SIgA amplification by oral administration of the ATP hydrolysing enzyme apyrase corrects enteropathic features of ICB and improves the therapeutic outcome. Consistent with SIgA function in reshaping the gut ecosystem and enhancing ICB, IgA-/- mice did not show any improvement of anti-tumor response by apyrase administration. Mechanistically, data in mouse and cancer patients suggest that invigorated enterotropic cytotoxic T cells expressing the chemokine receptor CCR9 replenish the tumor microenvironment (TME) in a CCL25-mediated fashion and control tumor growth, resulting in improved ICB efficacy.