Background Immune checkpoint inhibitors (ICIs) are limited by the high incidence of immune-related adverse events (irAEs) occurring in up to 40% of solid tumor patients on anti-PD-1 monotherapy 1 2 and 72% in anti-CTLA-4/anti-PD-1 combination.3 4 These toxicities can cause treatment cessation, hospitalization and even death.5–7 IrAEs are variable in severity, timing, onset, and remain poorly understood. Amongst the different toxicities, skin irAEs are most frequent, occur the earliest, and are correlated with a positive prognosis.4 8 However, there is a lack of preclinical models to study checkpoint toxicity. We evaluated a murine model of allergic contact dermatitis (contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8+ T cells to gain a mechanistic understanding of skin checkpoint toxicity.
Methods C57BL/6 mice (n = 5 per group) were sensitized epicutaneously on shaved flank with hapten 0.5% DNFB on day -5 and elicited on their ears with DNFB on day 0. Starting four weeks later, mice were treated with either anti-programmed cell death protein (PD-1) or isotype. At the time of the first recall challenge only, mice were given either anti-PD-1 or isotype. Mice received subsequent rechallenges with DNFB to the ears and ear swelling was measured at various time points. Mice were depleted of circulating or skin CD8+ T cells by anti-CD8 mAbs from day 29 onwards, and maintained weekly, as in this model CD8+ T cells are the main hapten responder population. Samples were collected for histochemistry and analyzed by flow cytometry.
Results Our data indicate that despite the depletion of circulating T cells, anti-PD-1 recipients mount a higher initial recall response to contact agents. Higher ear swelling was observed with increased inflammation in these mice. Our data suggest anti-PD-1 can liberate local T cell responses in the absence of a contribution from blood, and may offer a model to test therapeutic interventions to alleviate peripheral immune toxicities.
Conclusions Our results suggest that this murine model of contact hypersensitivity represents a potential model for skin immune checkpoint toxicities. This model of locally-mediated inflammatory recall may advance the goal of uncoupling toxicity from efficacy in patients with immune-related adverse events.
Ethics Approval The animal study was approved by Weill Cornell Medicine’s IACUC; approval number D16-00186.
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