Mechanisms of Immune-Related Adverse Events

The origins of immunotherapy can be traced back to the early 1900s when Paul Ehrlich postulated that the host immune system plays a role in the early recognition and elimination of malignant cells. Over the next century, many other researchers built upon this notion. Theories of immunosurveillance ^, and cancer immunoediting were conceptualized, to help explain the complex interplay between the immune system and carcinogenesis. ^, The theory of immunosurveillance proposed by Macfarlane Burnet and Lewis Thomas states that cellular immunity performs constant surveillance in the human body, and is able to identify and eliminate malignant cells in the early stages of carcinogenesis. This was followed by several experiments in murine models where the incidence of malignancies in athymic mice was studied by researchers. Unfortunately, these showed discordant results and failed to definitively show a relationship between immunosuppression and carcinogenesis. Interest in the role of immunity in carcinogenesis waned until the 1990s when new discoveries revived interest in this field.

It was during this time that better understanding of the complex interactions between the immune system and malignant cells led to the evolution of the theory of immunoediting. Immunoediting is best described by the three “E’s” which represent different stages in the process. The first “E” stands for “Elimination,” in which immune cells recognize and eliminate malignant cells. The second “E” represents “Equilibrium,” in which the tumor cell variants that escape elimination reach an equilibrium with the immune system. Although the immune system continues to evolve and destroy some of these variants, new variants of tumor cells are constantly being produced resulting in incomplete elimination and an equilibrium between the immune system and the tumor cells. A variety of cytokines and chemokines such as interferon γ, CXCL10, CXCL9, and CXCL11 produced by the tumor cells and the infiltrating immune cells modulate the interactions between the two in the tumor microenvironment. The third “E” stands for “Escape,” in which the tumor variants that have evolved to evade recognition by the immune system start to multiply rapidly. This escape is mediated by multiple modalities, such as loss of major histocompatibility complex (MHC) class 1 expression; antigenic mimicry; alteration of the chemokines leading to an increase in immunosuppressant cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs); and upregulation of the immune checkpoints leading to T cell exhaustion.

Early experiments that attempted to harness host immunity to combat cancer were performed as far back as 1777 when the surgeon to the Duke of Kent tried to create a cancer vaccine by injecting himself with malignant cells. These remained unsuccessful until 1891 when William Coley reported a 10% cure rate in soft-tissue sarcomas by using inactivated streptococci and Serratia marcescens . Over the next century recognition of the key role of cytokines led to the successful application of high-dose interleukin (IL)-2 in the treatment of melanoma and renal cell carcinoma. In the last decade, the field of immunotherapy has grown in leaps and bounds with the discovery of immune checkpoint inhibitors. In contrast to high-dose IL-2 which is associated with a number of serious adverse effects, these agents are much better tolerated. They have also shown remarkable efficacy in a wide range of malignancies and are currently approved for use in patients with advanced melanoma, non–small-cell lung cancer, head and neck squamous cell cancer, classic Hodgkin’s lymphoma, urothelial carcinoma, renal cell carcinoma, and advanced microsatellite instability (MSI) high/mismatch repair deficient tumors, among others. As immunotherapeutic agents interfere with the physiological pathways that regulate immune homeostasis, a spectrum of untoward side effects that resemble autoimmune diseases have been noted with their use. These adverse events are called immune-related adverse events or irAEs. In this chapter, we will explore the potential pathophysiological mechanisms leading to immune-related adverse events. We will begin by describing the physiological pathways responsible for immune tolerance and then go on to examine how alterations in these pathways can potentially lead to autoimmunity.

Both the innate and adaptive immune systems play an important role in generating immune responses in a normal host. Whereas the innate immunity is nonspecific and does not require antigen presentation by the MHC, adaptive immunity is more versatile and leads to the activation and expansion of antigen specific immune cells. Under physiological conditions, adaptive immunity is tightly regulated by costimulatory and inhibitory signals. T cell activation requires two signals—the first one is mediated by engagement of the T cell receptor with an antigenic peptide presented by MHC, and the second is mediated by binding of costimulatory molecules on T cells to ligands on antigen presenting cells. In naïve T cells, the interaction of the costimulatory CD28 with B7-1 and B7-2 (also known as CD80 and CD86, respectively) plays an important role in downstream signaling, which eventually leads to the secretion of proinflammatory cytokines such as IL-12 and interferon-γ, resulting in clonal expansion. The inhibitory signals allow for contraction of the T cell clone upon resolution of the antigenic stimulus.

The diversity of the T cell receptors (TCR) and B cell receptors (BCR) is a result of the recombination of three separate gene segments—the variable (V), diversity (D), and joining (J) genes—during the differentiation of B cells and T cells in the bone marrow (B cells) and thymus (T cells), respectively. Studies have estimated that between 20% and 50% of TCRs and BCRs generated by this process can have affinity to a self-antigen ; however, only a fraction of the general population develops clinical manifestations of autoimmunity. The inhibitory signals or immune checkpoints play an important role in immune tolerance of self-antigens by downregulation of the self-reactive cells. Some of the prominent immune checkpoints include cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), and lymphocyte-activation gene 3 (LAG3). Activation of T cells in the lymphoid organs leads to expression of CTLA-4, which is homologous to CD28 but binds to B7-1 and B7-2 with a much higher affinity than CD28, resulting in negative regulation of the T cell response. PD-1 plays an important role in regulation of T cell responses in peripheral tissues. PD-1 binds to its ligands PD-L1 and PD-L2 and leads to apoptosis of antigen-specific T cells and a reduction in the apoptosis of Tregs, therefore dampening the immune response.

Tumor cells can upregulate immune checkpoint pathways to evade the host immune system. Immune checkpoint inhibitors mediate their antitumor effects by releasing this inhibition and reinvigorating the immune responses to malignant cells. Predictably, this also interferes with the process of immune homeostasis as described previously and can result in immune-mediated adverse effects. The precise pathophysiology of irAEs is unknown; however, emerging evidence suggests that many different aspects of the immune system may play a role. In the following section, we describe the proposed mechanisms for irAEs and the evidence to support each of them.