# Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity

## TL;DR

This study reveals how the Notch signaling pathway is blocked during the uptake of dying cells by macrophages, which limits anticancer immunity.

## Contribution

The study identifies a mechanism involving integrin barriers and the Rubicon–VPS34 complex that actively suppresses Notch signaling during efferocytosis.

## Key findings

- Notch signaling is actively suppressed during efferocytosis by exclusion from the contact site.
- Activation of Notch in myeloid cells enhances anticancer immunity in mice.
- The Rubicon–VPS34 complex and phospholipase D regulate integrin activation to restrict Notch signaling.

## Abstract

The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active integrin barrier requires the Rubicon–VPS34 complex, which recruits phospholipase D (PLD) to regulate integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.

Here the authors show that during phagocytosis of dying cells anticancer Notch signaling is prevented by exclusion of its receptors on the macrophage at the contact site with the dying cell.