Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy

Abstract

Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.

Blood and guts: peripheral immune correlates of immunotherapy‐induced colitis

“…11 Treatment with ICB may represent a pharmacologic equivalent to genetic variants that break immune tolerance checkpoints. 12 The theory that multiple checkpoint breaks, both inherited and acquired, contribute to the development of autoimmune disease is consistent with the increased incidence of irAEs and improved cancer response rates seen in combination CTLA-4 and PD-1 blockade. 5 The findings here of a distinct immune profile in peripheral blood of individuals who go on to develop ICB-induced colitis may identify a population with genetic predisposition to gut autoimmunity-a group with low baseline tolerance thresholds, for whom the additional "insult" of ICB tips the balance toward breaking tolerance.…”

“…Preexisting autoimmune conditions, including ICB, are predictive of ICB toxicity; more than 30% of patients with preexisting autoimmunity will experience a flare on treatment 11 . Treatment with ICB may represent a pharmacologic equivalent to genetic variants that break immune tolerance checkpoints 12 . The theory that multiple checkpoint breaks, both inherited and acquired, contribute to the development of autoimmune disease is consistent with the increased incidence of irAEs and improved cancer response rates seen in combination CTLA‐4 and PD‐1 blockade 5 .…”

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurred in polyglandular endocrinopathies

“…Thyroid dysfunction is common in anti-PD1 induced irAEs [7,22]. T cells are believed to play a dominant role in destructive thyroiditis by anti-PD-1 [23]. Generally, the symptoms related to HT are mild [4] and treatment can begin when needed [20].…”

“…Destruction of β-cells was more severe in ICI-T1DM in comparison with classic T1DM [26]. In contrast, only 50% of patients with ICI-T1DM have a relevant autoantibody, with anti-GAD65 being the majority [23]. DKA at diagnosis is very frequent, up to 70% [7].…”

Thyroid-related adverse events induced by immune checkpoint inhibitors

“…The inhibitory effect on T-cell activity is obtained through binding of PD-1 to its ligands, which results in a decrease of glucose uptake and gluconeogenesis of T-cells and apoptosis, while also interrupting the co-stimulatory pathway of CD28-CD80/86 ( 11 , 12 ). Only regulatory T-cells will have an increased survival, as they have the ability to suppress cytotoxic CD8+ T-cell proliferation, in favor of immune escape of cancer cells ( 11 , 14 ). The PD-1 ligands seem to be present mostly in inflammatory settings as they are strongly regulated by interferon gamma ( 15 ): this could be a reason why chronic inflammation which surrounds tumors limits the destruction of cancer cells ( 16 ).…”