Immune-Related Adverse Events of Checkpoint Inhibitors and Human Leukocyte Antigen System: A Review

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Abstract: The introduction of immune checkpoint inhibitors (ICIs) in the treatment of cancer has significantly improved patient outcomes. Whereas ICIs have a substantially more beneficial risk profile than chemotherapy, immune-related adverse events (irAEs) are currently among the most pressing challenges of clinical oncology. It has been well established that certain variants of HLA genes are associated with increased susceptibility or a decreased risk of certain autoimmune diseases. Considering that irAEs often resemble autoimmune disorders observed in the general population, we conducted the first review summarizing the current knowledge on the link between the HLA system and the development of irAEs during ICIs treatment. We performed a comprehensive search of the US National Library of Medicine (PubMed) database. Based on the research conducted so far, our analysis indicates that certain HLA variants have been described to increase or, conversely, decrease the risk of irAEs. Thus, HLA genotyping may be useful in stratifying the risk of irAEs, allowing for more thorough screening of patients with a higher likelihood of developing ICI-related toxicities and less frequent monitoring of those at lower risk, thereby significantly reducing costs and the overall burden of disease. HLA genotyping may ultimately contribute to the personalization of cancer therapy, significantly improving patient safety and clinical efficacy. Furthermore, identifying an association between certain HLA variants and irAEs may lead to a better understanding of the pathogenesis underlying these adverse effects. Nevertheless, the studies conducted so far have included limited cohorts of patients with a wide variety of malignancies and diverse treatment regimens. Hence, further research that addresses these limitations is needed. Keywords: cancer, immune checkpoints inhibitors, ICIs, immune-related adverse events, irAEs, human leukocyte antigen, HLA

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