Checkpoint inhibition-induced sicca: a type II interferonopathy?

The advent of immune checkpoint inhibitor (ICI) therapy for treatment of cancers is unfortunately coupled with a broad panoply of side effects, related to non-specific activation of the immune system. One such side effect is the development of sicca complaints. This culminates in a proportion of patients who, according to the ACR-EULAR 2016 criteria, can be classified as suffering from the autoimmune disease primary Sjögren's syndrome (pSS). Although salivary gland (SG) loss of function is often seen after ICI therapy, the similarities with 'classical' pSS patients would appear to end there. Despite the presence of focal lymphocytic sialadenitis typical for SS in salivary gland biopsies from patients receiving ICI therapy, the nature of the immune infiltration (foci) following ICI use (T-cell dominated) is starkly different to that in pSS (B-cell dominated). The SG parenchyma post-ICI use does not present with germinal centres, lymphoepithelial lesions or IgG plasma cells, which are frequently found in the SG in pSS. Here we review the functional deterioration of SGs following ICI use, the SG parenchyma phenotype associated with this, and ultrasound abnormalities. We conclude by suggesting that ICI-induced SG dysfunction may represent a new interferonopathy, driven by IFNγ, and that this 'pSS' patient cohort may require a different management than classical pSS patients.