Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma

Simple Summary Granulomatosis is commonly observed in patients receiving immune checkpoint inhibitors (ICIs) for melanoma and other cancers. Recognizing this reaction early is critical to avoid confusing it with cancer progression. Our objectives were to characterize instances of granulomatosis triggered by immunotherapy, to question their relationship with sarcoidosis, to explore their potential pathophysiological mechanisms and to address the possibility of an association between such events and response to immunotherapy. Our work is based on a retrospective study of 18 cases and on a thorough review of the literature of melanoma patients developing ICI-associated granulomatosis. After analyzing the clinical, histopathological and biological results, we propose that immuno-induced granulomatosis corresponds to an experimental sarcoidosis and should be considered as an ICI-associated effect rather than a severe immune-related event. Indeed, ICI-associated granulomatosis seems to be associated with a good ICI response and usually does not require ICI interruption or symptomatic treatment. We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this "experimental" sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition.