Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors

Abstract

Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors [e.g., human leukocyte antigen (HLA)] was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis.

Keywords: CTLA-4; HLA; NMDAR; PD-1; autoimmune encephalitis; immune checkpoint inhibitors; neurological adverse events; paraneoplastic neurological syndromes.

Figure 1.

Tumor genetic alterations leading to immune tolerance breakdown in PNS. The model of PCD is shown since it is the only one in which genetic studies on PNS-related tumors have been performed. Three main mechanisms are presented: somatic mutations, gene amplification, and protein overexpression. These processes are not mutually exclusive. HER2, human epidermal growth factor receptor 2; PCD, paraneoplastic cerebellar degeneration; PNS, paraneoplastic neurological syndrome.

Figure 2.

Proposed mechanisms of neurological irAEs triggered by ICIs. (A) PNS-like mechanism. An immune-response against a shared auto-antigen between the tumor and neural tissue is triggered by ICIs. In the periphery, tumor-related antigens (including mutant forms of onconeural proteins) are released after immune attack by NK-cells. Onconeural antigens are then phagocytosed and presented by APCs to cells of the adaptive immune system. CD4+ helper T cells play a key role in activating B cells, which are then able to differentiate into antibody-producing plasma cells. Antigen-specific CD8+ cytotoxic T cells are also primed by APCs and represent the main effectors of neuronal damage. (B) Flare of a latent autoimmune condition. In this hypothesis, immune breakdown is already present and ICI stimulate the brain immune-reaction. (C) Direct complement-dependent or cell-dependent cytotoxicity. CTLA-4 is expressed on pituitary cells and ICI treatment can trigger complement-mediated direct damage, explaining the high rate (approximately 10%) of hypophysitis in patients treated with anti-CTLA4 Abs (ipililumab). (D) Interplay between previous viral infection and irAE. Oligoclonal activation of CD4+ T cells specific for a viral pathogen (e.g., EBV) in the presence of ICIs. Abs, antibodies; Ag, antigen; APC, antigen-presenting cell; CTLA4, cytotoxic T-lymphocyte antigen 4; EBV, Epstein-Barr virus; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; MHC, major histocompatibility complex; NK-cell, natural killer cell; PD-1, programmed cell death protein 1; PNS, paraneoplastic neurological syndrome; TCR, T-cell receptor.

Figure 3.

Schematic representation of the four known triggering factors in PNS and AE. AE, autoimmune encephalitides; CASPR2, contactin-associated protein-like 2; GAD, glutamic-acid decarboxylase; HLA, human leukocyte antigen; HSV, herpes simplex virus; IgLON5, immunoglobulin-like cell adhesion molecule 5; LGI1, leucine-rich glioma-inactivated 1; NMDAR, N-methyl-D-aspartate receptor; NSCLC, non-small-cell lung cancer; PNS, paraneoplastic neurological syndromes; SCLC, small-cell lung cancer.