*4.7. Immunomodulation*

There is currently insufficient research regarding the role of immunomodulation in IR-induced salivary gland dysfunction or in models of IR-induced bystander effects to fully define the role of P2 receptors. A T cell-mediated mechanism of long-distance effects on metastatic lesions following irradiation of primary tumors—coined the abscopal effect—has been described [169–171]. Most bystander effect studies are performed in vitro, making it difficult to ascertain the contributions of various immune cells that recapitulate in vivo conditions [172]. However, one study utilized an in vivo model of radiation-induced acute myeloid leukemia to investigate the bystander effect. They found that the long-term bystander consequences of irradiation in vivo were due to altered macrophage activity [172]. P2Y2R signaling pathways are involved in the recruitment, migration and proliferation of immune cells [173–175], and thus activation of this receptor by elevated eATP levels following IR should mediate the modification of the immune landscape in the salivary gland.

In conclusion, the available data strongly support the notion that purinergic signaling plays a role in the IR-induced bystander effect in multiple models. In particular, the role of P2X7R, P2X4R, and P2Y2R, given their reported expression in human and mouse salivary glands, should be further investigated for their potential as novel targets for the prevention of the bystander effects underlying IR-induced salivary hypofunction.
