Abstract
Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.
Highlights
The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of cancer care, since immunotherapeutic strategies are emerging as potentially curative systemic therapy for several tumors, especially for tumor types traditionally known to have poor outcomes
Increased circulating levels of IL-6 and C-reactive protein (CRP) have been recorded in patients with different tumor types developing a broad range of immune-related adverse events (irAEs), and a synergistic antitumor activity has been demonstrated in mouse models combining ICIs with inhibition of the IL-6 axis (Esfahani et al, 2020a)
Distinct human leukocyte antigen (HLA) haplotypes, and polymorphisms in immunoregulatory genes such as Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and Programmed cell death 1 (PD-1) have been associated with a variety of classical autoimmune diseases, and likely play an important role in the development of irAEs (e.g., HLA-DQ8 and HLA-DR53 for lymphocytic hypophysitis), and the predominance of HLA-DR4 among patients treated with PD1- or programmed death-ligand 1 (PD-L1)-directed ICIs developing autoimmune insulindependent diabetes (Khan et al, 2018))
Summary
The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of cancer care, since immunotherapeutic strategies are emerging as potentially curative systemic therapy for several tumors, especially for tumor types traditionally known to have poor outcomes. Combination strategies (PD-1 or PD-L1 agents with other immunotherapy agents such as anti-CTLA-4 antibodies, molecular targeted therapy, vaccines, chemotherapies, radiotherapy, or chemoradiotherapies) may improve outcomes, as supported by recent evidence of superior treatment responses and patient survival. Several factors may influence the development of irAEs during treatment with ICIs, including the cancer type, molecular target PD-L1), single agent administration or combined checkpoint blockade and/or sequential use of different types of ICIs. Treatment duration and prior chemotherapy likely influence immunotherapy tolerance, together with underlying host factors such as the patient’s age, genetic predisposition to autoimmunity and/or pre-existing autoimmune disorders, and the host microbiome (Weinmann and Pisetsky, 2019). The aim of our work was to provide an overview of the current evidence on the biological bases underlying irAEs, and to speculate about possible crosslinks with radiation-induced anticancer immune responses
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