Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors

Abstract

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.

Understanding Checkpoint Inhibitors in Cancer Therapy, Mechanisms of Action, Resistance and Future Challenges

“…However, PD-1 and PD-L1 inhibitors exert the effects on T-cells within end tissues such as the lung, gastrointestinal, thyroid, skin or the liver [46]. This difference in the irAES between CTLA-4 and PD-1 blockade are consistent with data from murine deficient models CTLA-4 and PD-1 [45]. Deficiency of CTLA-4 in mince is rapidly lethal and precipitate with early onset of progressive lymphoproliferative disorders with infiltration of multiple organs by polyclonal T cells, whereas PD-1 knocked out mice had near normal life span develop a more insidious and slowly progressive autoimmune disorders such as rheumatoid arthritis and dilated cardiomyopathy [47][48][49].…”

“…The core mechanism of irAES of ICIs is the ability of this class of drugs to unleash cellular immunity and disruption to immunologic selftolerance [44]. ICIs also stimulate B cells to produce autoantibodies which contribute to the development of irAES [45].…”

<p>Association Between RBC Antigen Allo-Antibodies and Immune-Related Adverse Events During Immune Checkpoint Inhibitor Treatment for Advanced Cancers</p>

“…The possible mechanisms may be inferred from other common ipilimumab-associated irAEs studies. 27 Treg identified as CD4+ FOXP3+ T cells produce IL-10 as a way to suppress effector T cells and thus prevent autoimmunity. 28 Anti-CTLA4 (cytotoxic T-lymphocyteassociated protein 4) causes loss of Treg, which is thought to cause irAE, including immune cytopenias and AIHA.…”

Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

“…18 Treatment of inflammatory arthritis included nonsteroidal anti-inflammatory drugs (NSAIDs), prednisone, and both nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs). 19 Hematological irAEs, including autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia and aplastic anemia, are rarely reported. Surveillance of the complete blood count is essential.…”