SP0177 IMPACT OF CHECKPOINT INHIBITORS ON B CELLS
Authors: David Pisetsky
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Immune checkpoint inhibitors (ICI) are a new class of biological agents that has revolutionized the treatment of cancer. Unlike conventional cytotoxic agents that are designed to kill cells, ICI block interactions that regulate the T cell response to cancer. At present, two classes of ICI are available to treat a wide variety of malignancies: antibodies to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and antibodies directed to the programmed death-1 (PD-1) and PD-1 ligand (PD-L1) axis, either to PD-1 or PD-L1. While both anti-CTLA-4 and antibodies to PD-1/PD-L1 are effective, these systems differ in the T cell populations affected, the location of these cells and the downstream signaling pathways involved. ICI can be used alone or in combination. Despite differences in mechanism of action, treatment with both types of ICI is associated with severe side effects that have been termed immune-related adverse reactions (irAE). irAE include, among other manifestations, dermatitis, colitis, pneumonitis, endocrinopathy (hypothyroidism, hypophysitis, adrenal insufficiency) and arthritis and related conditions. Because of the goal of ICI therapy is the induction or stimulation of cytotoxic T cells, the effect of these agents on B cells has received much less attention. In general, effects of ICI on tumors are considered the action of T cells. irAE, however, may result from B cell effects and the induction of autoantibodies. Thus, autoantibodies to thyroid antigens may lead to thyroiditis and subsequent hypothyroidism. Similarly, ICI can lead to the production of antibodies to islet antigens as well as glutamic acid decarboxylase 65 and induction of diabetes. On the other hand, while arthritis can be an irAE, affected patients usually do not show antibodies to citrullinated proteins (ACPA). Importantly, functional and phenotypic properties of B cells following ICI may help predict the emergence of irAE. Much of the data on this issue comes from a detailed analysis of patients with melanoma treated with anti-CTLA-4, anti-PD-1 or the combination. With this combination, B cells of treated patients showed characteristic changes that include a decrease in the number of circulating B cells in conjunction with an increase in plasmablasts and a population of B cells characterized by low expression of CD21. Furthermore, in treated patients, the CD21<sup>lo</sup> B cells population showed greater clonality as well as a higher frequency of clones in comparison to the CD21<sup>hi</sup> population. These changes, which may resemble those seen in patients haploinsufficent for CTLA-4, may predict the development of irAE. The CD21<sup>lo</sup> B cell population may have a particular role in the development of irAE since these cells appear to be recent emigrants from germinal centers and may undergo rapid activation. The effects of ICI on B cell populations is also relevant for ICI use in the setting of pre-existent inflammatory or autoimmune disease marked by autoantibody production. While ICI, either alone or in combination, can lead to the exacerbation of these conditions, the effect on autoantibody production has not yet been well studied. These exacerbations, however, can respond to agents such as glucocorticoids or TNF blockers whose B cell effects are not clear. Since B cells can express PD-1 as well as PD-L1, the effects of ICI may direct actions or the indirect effects on other cell populations. Future studies are needed to delineate more precisely the contribution of B cells to the response of cancer to ICI as well as the development of irAE. <h3>Disclosure of Interests:</h3> None declared