Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.

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Immune checkpoint inhibition has resulted in significant efficacy across many cancer types, including melanoma. Melanoma is the second most common cancer among those of reproductive age, yet the reproductive toxicities of adjuvant and first-line immunotherapy are largely unknown.The normal innate and adaptive immune systems play a vital role in reproductive organ homeostasis of men and women and are essential for implantation, fertility, and a successful pregnancy. The programmed cell death-1 receptor/programmed cell death receptor ligand-1 (PD-1/PD-L1) pathway is essential in several aspects of fertility and pregnancy. Recent studies have largely focused on the role of the PD-1/PD-L1 pathway in fetomaternal tolerance, highlighting the importance of intact immune regulation in promoting a successful pregnancy.In this review, we describe a case of a reproductive-aged female with stage IIIC melanoma who sought guidance on family planning after pembrolizumab therapy. We discuss the known fertility-related toxicities of immune checkpoint inhibitors, the potential targets for reproductive toxicity in males and nonpregnant females, and the implications of anti–PD-1 therapy in relation to fetomaternal tolerance. Informed decision making will benefit from data and consensus.

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