Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review

Abstract

Immune checkpoint inhibitors have emerged as a remarkable treatment option for diverse cancer types. However, a significant number of patients on checkpoint inhibitors develop immune-related adverse events (irAEs) affecting a wide variety of organs. These events, which may reflect enhanced T cell activation, are unpredictable, heterogeneous, and in some instances permanent or life-threatening. It is not clear whether these toxicities are distinct from conventional autoimmune diseases or whether the manifestation of irAEs is associated with therapeutic efficacy. Studies across the spectrum of basic, preclinical and clinical research deciphering the role of genetics, epigenetics, gut microbiota and underlying immune status of patients who develop irAEs are required to gain a deeper mechanistic understanding. Insights gained from such studies will facilitate identification of biomarkers for optimal treatment and clinical management of patients. In this Review, we provide basic and clinical understanding of immune checkpoint inhibitors and irAEs. We discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; insights into potential underlying mechanisms of irAEs; impact of autoimmune diagnosis on cancer outcome; and management of irAEs.

Keywords: Autoimmunity; Immune checkpoint inhibitors; Immunotherapy; Toxicity and irAEs.

Figure 1.

Spectrum of immune-related adverse events (irAEs) in patients receiving checkpoint inhibitor therapy.

Figure 2.

Left Panel: Schematic representation of mechanism of action of CTLA4 (Top) and PD-1 (Bottom) mediated inhibition of T cell activation. Right Panel: Potential mechanism of action of anti-CTLA-4 blockade (Top Panel) and anti-PD-1/anti-PD-L1 blockade (Bottom Panel) in mediating anti-tumor activity. CTLA4: cytotoxic T-lymphocyte–associated protein 4; irAE: immune-related adverse event; PD-1: programmed death-1; PD-L1: programmed death-ligand 1; Treg: regulatory T cell; APC: Antigen Presenting Cell; MHC: Major histocompatibility complex; TCR; T-cell receptor.

Figure 3.

Future studies to increase the mechanistic understanding of development of irAEs across the spectrum of basic, preclinical and clinical research. Longitudinal assessments of changes in immune system at baseline, during, and post therapy could reveal important insights to facilitate the development of biomarkers for diagnosis, treatment and management of irAEs. irAE: immune-related adverse event.