Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

Keywords: aspergillus lung disease; bacterial infection; lung cancer; lung cancer chemotherapy; opportunist lung infections; tuberculosis; viral infection.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart.

Figure 2

Spectrum of immunotherapy-associated infections. While immunosuppression alone can cause infectious complications, the dysregulated immunity that results from immune checkpoint inhibition can lead to different patterns of infection reactivation due to excessive inflammation, thereby resulting in a spectrum of disease phenotypes. ITI-DI, immunotherapy infections due to dysregulated immunity; ITI-IS, immunotherapy infections due to immunosuppression; Mtb, Mycobacterium tuberculosis; C diff, Clostridium difficile; CMV, cytomegalovirus; HBV, hepatitis B virus.

Figure 3

Development of pulmonary TB on triplet chemotherapy. Comparison of diagnostic CT scan performed 2 weeks before treatment (A) with the CT scan at the time of TB diagnosis (B) shows regression of the tumour with immune checkpoint inhibition but new consolidation with cavitation. Adapted from Crawley et al.

Figure 4

Development of pulmonary Aspergillus infection on nivolumab treatment. Original publication: adapted from Inthasot et al, reproduced with permission from the publisher.

Figure 5

Potential mechanisms whereby ICIs may lead to reactivation of infection and immune-related tissue damage. Sustained antigen exposure from persistently infected cells can cause an overexuberant immune response harmful to the host. ICs may regulate homeostasis in latent infection, while signalling disruption with ICIs may promote excessive inflammation, infection reactivation and immunopathology. IC, immune checkpoint; ICI, immune checkpoint inhibitor; IL, interleukin; PD-1, programmed cell death protein 1.