LAUSR

events of PD-1 immunotherapy are being increasingly reported and characterized. Since our initial publication, additional cases of eruptive KAs have been reported, supporting its status as an associated adverse event. It is encouraging to see these reports so that we can better characterize the adverse event profile and gain insight into pathogenesis. It is unclear exactly why KAs paradoxically erupt secondary to a medication used to treat squamous cell carcinomas (SCCs) of the lung and head/neck. It is further confusing in the light of a recent publication reporting very similar PD-L1 expression profiles between KAs and cutaneous SCCs. Nevertheless, the eruption of KAs in PD-1 immunotherapy may prove fortuitous by providing new insight into their unique biology. Although KAs may simply represent a well-differentiated variant of SCC, many consider them a distinct entity – a notion supported on the molecular level. We know PD-1 inhibitors enhance antitumour activity by blocking the immune downregulation that occurs when PD-1 on T cells binds its ligands, often strategically overexpressed on malignant tumour cells. However, antitumour activity is not the only T-cell function ‘unchecked’. Tcell receptor signalling, cytokine production, lymphocyte motility and metabolic programming are all ‘unchecked’ by inhibiting PD-1. Perhaps then KAs are closer related to a reactive proliferation akin to exuberant squamous metaplasia, and a pro-inflammatory cytokine milieu injures predisposed keratinocytes in a way that incites a reactive proliferation that outpaces any enhanced antitumour activity. In the same vein, increased cytokine production (e.g., IL-2, IL-4) could tip a precarious inflammatory balance towards Th1 (lichenoid dermatitis, vitiligo) or Th2 (antibody-related disease) pathways. Further investigation into these immune-related adverse events is certainly needed and might include the immunohistochemical characterization of the inflammatory infiltrate before, during and after immunotherapy. Such information may provide further insight into pathogenesis as well as possible immunohistochemical methods for monitoring treatment efficacy and progress.