Abstract
Blockade of PD-1, an indispensable physiological immunoregulatory mechanism, enhances immune activities and is widely used in the immunotherapy of cancer. This treatment often accompanies inflammatory complication called immune-related adverse events (irAE), most frequently in the skin. To analyze how skin inflammation develops by the blockade of PD-1-dependent immunoregulation, we studied the exacerbation of oxazolone-induced contact hypersensitivity by PD-L1 blockade. The inactivation of PD-1 signaling enhanced swelling of the skin with massive CD8+ T cell infiltration. Among PD-1-expressing cells, T cells were the predominant targets of anti-PD-L1 mAb treatment since PD-L1 blockade did not affect skin inflammation in RAG2-/- mice. PD-L1 blockade during immunization with oxazolone significantly promoted the development of hapten-reactive T cells in the draining lymph nodes. The enhancement of local CD8+ T cell-dominant immune responses by PD-L1 blockade was correlated with the upregulation of CXCL9 and CXCL10. Challenges with a low dose of oxazolone did not demonstrate any significant dermatitis; however, the influence of PD-L1 blockade on T cell immunity was strong enough to cause the emergence of notable dermatitis in this suboptimal dosing, suggesting its relevance to dermal irAE development. In the low-dose setting, the blockade of CXCR3, receptor of CXCL9/10, prevented the induction of T cell-dominant inflammation by anti-PD-L1 mAb. This experimental approach reproduced CD8+ T cell-dominant form of cutaneous inflammation by the blockade of PD-L1 that has been observed in dermal irAE in human patients.
Highlights
The immune system has its own regulatory mechanisms with which the intensity of immune responses is modulated at proper levels
PD-1-dependent immunoregulation plays a key role in cutaneous inflammation
Oxazolone alone did not change the chemokine mRNA levels compared to untreated controls. (G, H) Anti-CXCR3 mAb suppressed the induction of era swelling (G) and T cell accumulation (H) by the suboptimal exposure to oxazolone (20 μg) plus PD-L1 blockade
Summary
The immune system has its own regulatory mechanisms with which the intensity of immune responses is modulated at proper levels. Since some of these mechanisms are exceptionally important, the deficiency of one of such immunoregulatory mechanisms may not be compensated by all of the rest. PD-1 represents the indispensable immunoregulatory mechanisms that spontaneously downregulate immune responses. PD-1 expression is not detectable in most resting T cells, but it is notably induced upon activation. This expression pattern indicates PD-1’s function as a negative feedback mechanism in activated immune cells. PD-1deficiency causes various autoimmune disease-like symptoms in different organs [1,2,3]
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