Immunotherapy has transformed the treatment of cancer by restoring the power of the immune system against tumor cells. CTLA-4 blockade supports activation and proliferation of effector T cells and shuts down immunosuppressive regulatory T cells. PD-1 blockade synergistically enhances peripheral T-cell proliferation, function and stimulatory cytokine production . Check point inhibitors (CPIs) have become the standard care in the treatment of a melanoma , non-small cell lung carcinoma [3,4], bladder [5,6], renal cell carcinoma [7,8] and more, introducing a dramatic survival benefit (Fig. 1). Disruption of the innate immune system inhibition has introduced a class effect: a large and growing spectrum of autoimmune diseases termed immune-related adverse effects (irAEs) [9e11]. IrAEs induced by CPIs are generally regarded as idiosyncratic, but accumulating evidence indicates that irAEs occurrence depends on a host's propensity for autoimmunity, the type of immunotherapy agent(s) used, and the duration of treatment [10,12]. Some organs are prominent targets to the dys- regulated immune activity, specifically the skin, endocrine and alimentary systems [13e16]. Besides their prominent prevalence, CPI-induced endocrinopathies are characterized by a unique course, being mostly irreversible and unresponsive to glucocorticoid immunomodulation, in contrast to most im- mune related adverse effects (irAE). What makes the endocrine system such a prominent autoimmune target when facing an unleashed immune system? Why are these autoimmune injuries mostly irre- versible and unresponsive to glucocorticoid therapy? Is it possible to identify those prone to develop irAEs in general and endocrinopathies particularly? What are the correlations between irAE and dis- ease response and survival? The present review describes the unique characteristics of the endocrine system and its crosstalk with the immune system in an attempt to shed light on these questions and introduce opportunities for novel research directions. The crosstalk between genetic autoimmune predisposition and immune ignition by check-point inhibition Autoimmune diseases are heavily dependent on genetic propensity depending on genetic loci related to immune regulation, including variations in the HLA-DR system, a class II HLA gene that plays
a critical role in antigen presentation. In humans, this genomic locus is known as the human leukocyte antigen (HLA) system, which encodes mostly immune associated proteins whose main role is the presentation of antigens to the immune cells. This system is essential for the proper immune response against pathogens and is strongly implicated in the development of autoimmune diseases. Hundreds of polymorphisms of HLA-DRB1 have been associated with the immune response to infection as well as with different autoimmune disorders  as well as with immune response to infection. Recently, the mechanism by which HLA DRB1 haplotypes render an individual to be at a higher risk for autoim- munity was deciphered. These haplotypes, which are associated with an aggressive immune response, possess an evolutionary advantage, i.e.
defending against enteric fever, yet putting them at an increased risk for autoimmunity when an external dysregulation of the immune system occurs [18,19] (Fig. 2).
Endocrinopathies induced by check point inhibitors
Thyroiditis is by far the most prevalent and reported irAE, occurring in up to 30% of CPI treated patients [12,20,21] whereas type-1 diabetes mellitus is relatively rare with an estimated prevalence of 0.5e1.9% [9,22e25]. Autoimmune hypophysitis has been predominantly associated with CTLA-4 in- hibition, either alone or in combination with PD-1/PD-L1 inhibition, with a prevalence of about 8% [26,27]. Adrenalitis has been reported scarcely with an estimated prevalence of 0.5%  while isolated ACTH deficiency (IAD) causing a secondary adrenal insufficiency with otherwise intact pituitary function, has been recently reported as the predominant CPI induced disease the hypothalamic- pituitary-adrenal (HPA) axis [29e34]. There are rare reports of central diabetes insipidus due to an autoimmune damage to the posterior pituitary  and
hypoparathyroidism  (Fig. 3).
The endocrine system functions in synchronization to regulate hormone production and secretion. As dictated by this physiologic role, the endocrine glands represent a highly communicative network with an intensified signaling load and antigen versatility  Self-antigens are conventionally subject to immune tolerance and therefore induce weak or no CD8 T cell responses but bear the potential to magnetize dysregulated T cells provoked by CPIs. Anti-thyroid antibodies are highly prevalent in the
diabetes under check point inhibition express glutamic acid decarboxylase (GAD-65) antibodies, islet cell antibodies (ICA) antibodies, insulin autoantibodies (IAA) or IA-2A antibodies against tyrosine phosphatase [9,22e25]. The correlation between thyroid antibodies and CPI induced thyroiditis is similarly redundant [20,21]. Are there additional autoantibodies to beta cells of the pancreas? What are the antibodies involved in CPI-induced pituitary and adrenal autoimmunity? Are these the known antibodies POMC/ACTH//TPIT/PIT1 and 21-hydroxylase antibodies, respectively  or other anti- bodies, yet to be discovered?
The endocrine glands reside on relatively small tissue reservoirs scattered throughout the body and hence, are more vulnerable to an autoimmune attack. Once immunologically damaged, endocrine glands are less likely to regenerate and restore function compared to larger organs. The thyroid gland is a bold example for this principle, as the majority of CPI induced thyroiditis evolve to permanent hy- pothyroidism. In the classic Hashimoto's disease, cytotoxic T cells target the thyroid gland by auto- immune antibodies (anti-thyroperoxidase and anti-thyroglobulin antibodies) and the disease may evolve in various paces and extents: from a partial, intermittent thyroid insufficiency to a complete elimination of thyroid function, depending on the magnitude of cytotoxic recruitment against the thyroid tissue. In contrast, the immune dysregulation induced by CPIs elicits a robust cytotoxic activity leading to rapid and complete tissue consumption in the majority of cases. CPI induced central diabetes insipidus, i.e. autoimmune insult to the posterior pituitary gland and parathyroid injury are irreversible [35,36,43,44], in accordance with proposed reservoirevulnerability correlation. CPI induced diabetes follows the irreversibility rule of endocrinopathies, since the overall size of the pancreas is misleading: the net beta cell mass amounts to 0.8e1.2 g in average . Pituitary and adrenal endocrinopathies, i.e. hypophysitis, isolated adrenocorticotrophic hormone (ACTH) deficiency (IAD) and adrenalitis are challenging to determine whether persistent or potentially transient. Due to the negative inhibition feedback loop of cortisol on the hypothalamus and pituitary and the trophic dependence of the adrenal gland on ACTH, hormone replacement therapy interferes with the possibility for adrenal regeneration [9,46e48]. However, they are mostly considered irreversible. As a whole, CPI induced endocrinopathies evolve more rapidly than the classic autoimmune diseases. A demonstrative difference is reflected in immune related adrenalitis, which evolves within a few months compared to the classic Addison's disease, developing over a 5e20 years' course [49,50]. This difference probably represents the robust and aggressive immune recruitment induced by CPIs.
Better understanding of the complex cross talk between genetic autoimmune determinants and check point inhibition, based on genome-wide association study (GWAS) and whole exome sequencing waits for translation to personalized medicine. A genome based autoimmune predictive matrix will optimize the use of the CPI double edge sword by minimizing the risk for irAEs and maximizing efficacy
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