Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors

Abstract

The introduction of immune checkpoint inhibitors (ICIs) in oncologic therapies has led to a paradigm shift in cancer treatment. ICIs have increased the overall survival in patients with malignant melanoma, small-cell lung cancer, and many other tumor entities. Despite their clinical benefits, these novel cancer immunotherapies can induce neurological immune-related adverse events (irAEs). Such immune-mediated complications can manifest within the spectrum of paraneoplastic neurological syndromes (PNSs). PNSs are rare immune-mediated complications of systemic cancers that can involve every aspect of the nervous system. The emergence of PNSs with ICI treatment opens further pathways to study the complex immunopathological interplay of cancer immunity, cross-reactive neurological autoimmune phenomena, and effects of ICIs on the immune system. ICI-induced PNSs comprise a diverse antibody repertoire and phenotypic spectrum with severe and life-threatening disease progression in some cases. Timely diagnosis and urgent interventions are pivotal for a favorable neurologic and oncologic outcome. This review focuses on the pathogenesis of cancer immunotherapy and the disruption of immune tolerance in PNSs and provides an overview of the most pertinent clinical manifestations and principles of diagnostic and therapeutic managements in light of the expected increase in PNSs due to the widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs.

Keywords: Autoantibodies; Biologicals; Immune checkpoint inhibitors; Neurological adverse events; Novel immunotherapies; Paraneoplastic neurological syndromes.

Fig. 1

Proposed pathogenic mechanisms of immune checkpoint-inhibitor (ICI)-induced paraneoplastic neurological syndromes (PNSs) and therapeutic strategies. The induction of immune-mediated PNSs under ICI therapy is a multistep process, resulting in the accumulation and amplification of autoreactive cellular and humoral immune responses directed against the central nervous system (CNS) and peripheral nervous system. Tumor neoantigens are released upon tumor necrosis (1). Dendritic cells capture, process and present these cancer-derived neoantigens on major histocompatibility complex (MHC) molecules to naïve T cells in the lymph nodes (2). Recognition of intracellular neuronal antigens (red ovoid shapes) activates CD8⁺ cytotoxic T cells, giving rise to T cell-mediated PNSs (2a). Cell surface neuronal antigens (green ovoid shapes) are recognized by CD4⁺ T helper cells that then activate memory B cells and antibody-producing plasma cells, driving antibody-mediated PNSs (2b). ICIs are monoclonal antibodies (mAbs) that block co-inhibitory signals of T cell activation, including the cytotoxic T lymphocyte antigen 4 (CTLA-4) (2a + b), programmed cell death 1 (PD-1) or its ligand PD-L1 (5), resulting in enhanced T cell activation and proliferation. In addition to cellular changes, ICIs increase the production of pro-inflammatory cytokines (3), which can further promote T cell proliferation (4). Tumor-infiltrating effector CD8⁺ T cells recognize the cognate antigen, which is presented by MHC I molecules on tumor cells, leading to tumor cell killing (5). If CD8⁺ cytotoxic T cells and antibody-secreting plasma cells travel to the nervous system, they can induce PNSs manifesting as immune-related adverse events (irAEs) under ICI therapy. Autoreactive cytotoxic CD8⁺ T cells can cross the blood–brain barrier (BBB) and cause direct cytotoxicity and irreversible neuronal cell death in the CNS (6). Autoantibodies targeting cell surface neuronal antigens can cause cell damage via modulation of protein expression and function, antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC) in the CNS (6) or the peripheral nervous system (7). Endothelial cells can recycle immunoglobulin G (IgG) autoantibodies with the neonatal Fc receptor (FcRn) that prevents lysosomal degradation upon binding to the antibody, further contributing to antibody-mediated neuronal damage (8). Therapeutic strategies (red) are guided by the pathogenesis of the PNS and aim at reducing disease-driving autoreactive cytotoxic T cells (orange boxes) or autoantibodies (blue boxes) (see main text for details). Some therapeutic options reduce both pathogenic T cells and autoantibodies (mixed orange and blue boxes). ADCC, antibody-dependent cellular cytotoxicity; APC, antigen-presenting cell; C, complement component; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CTLA-4, cytotoxic T lymphocyte-associated antigen; FcRn, neonatal Fc receptor; ICI, immune checkpoint inhibitor, IL, interleukin; mAb, monoclonal antibody; MAC, membrane attack complex; MHC, major histocompatibility complex; NK, natural killer cell; PD-1, programmed cell death protein 1 receptor; PD-L1, programmed cell death protein ligand 1; TCR, T cell receptor VCAM-1, vascular cell adhesion molecule-1. Created with BioRender.com