Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Abstract

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Keywords: ICI; anti-CTLA4; anti-PD1/PD-L1; immune checkpoint inhibitors; immune-related adverse events; irAEs.

Figure 1

Programmed cell death protein ligand 1 (PD-L1) expression in tumor cells and immune infiltrate. (A) Esophagus squamous cell carcinoma 2.5 × Hematoxylin-eosin stain: neoplastic cells (circled), inflammatory infiltrate (arrows). (B) Esophagus squamous cell carcinoma 20× stained with monoclonal antibody anti-PD-L1. (C,D) Esophagus squamous cell carcinoma 40× stained with monoclonal antibody anti-PD-L1. Arrow: membrane positivity of neoplastic cell. Arrowhead: membrane positivity of immune infiltrate. (E) Lung adenocarcinoma 40× stained with monoclonal antibody anti-PD-L1. Arrow: membrane positivity of neoplastic cell. Arrowhead: membrane positivity of immune infiltrate.

Figure 2

Immunological mediators and molecular mechanisms driving ICI-induced irAEs. Loss of immune checkpoint inhibition induced by ICI usage results in the diversification of T- and B-lymphocyte populations, with the consequent expansion of autoreactive clones that mediate direct damage to the tissues via production of inflammatory cytokines/chemokines and autoAbs. Alternatively, tumor cells release self-antigens following cytotoxic attack, which lead to cross reactivity with antigens found in normal tissues. Additionally, ICIs can mediate tissue damage via direct off-target binding to tissues expressing CTLA4. APC, Antigen Presenting Cell; MHC II, Major Histocompatibility Complex class II; TCR, T-cell receptor; CD4, Cluster of differentiation 4; CTLA4, Cytotoxic T-Lymphocyte Antigen 4; PD1, Programmed cell death 1; PD-L1, Programmed cell death ligand 1, CD8, Cluster of differentiation 8; MHC I, Major Histocompatibility complex class I; BCR, B-cell receptor; IL, interleukin; TNF, tumor necrosis factor; GM-CSF, Granulocyte–Macrophage Colony-Stimulating Factor. Created with BioRender.com.

Figure 3

Risk profiles of immune-related adverse events (irAEs) by different immune-checkpoint inhibitors (ICIs). Representative irAEs from two systematic reviews are reported [30,109]. These irAEs have been grouped per type of organ involved. The frequency of occurrence is coherent with the length of the bars. The colors are indicative of the major involvement of a specific ICI: red indicate that the immune toxicity is more commonly associated with the use of anti-CTLA-4; blue indicate that the toxicity is more commonly associated with the use of PD1/PD-L1 inhibitors. Every category is the sum of all the system features, e.g., neurological irAE includes myositis (very frequent event, more often PD1-mediated) and meningitis (very rare event, more often CTLA4-mediated); therefore, the localization of the neurological irAE closer to PD1/PD-L1 instead of CTLA4 is driven by the higher frequency of myositis in this category.