Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

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.

Stereotactic Body Radiation Therapy (SBRT) for Oligorecurrent/Oligoprogressive Mediastinal and Hilar Lymph Node Metastasis: A Systematic Review

“…However, others warn of possible immune-related adverse events and a synergistic effect of radiotherapy and immunotherapy on toxicities [ 69 ]. Moreover, the addition of SBRT could trigger a reactivation of the immune response in patients who are no longer responsive to immunotherapy, triggering an ex novo immune response [ 70 ].…”

Linac-based stereotactic salvage reirradiation for intraprostatic prostate cancer recurrence: toxicity and outcomes

“…Emerging data have established RT as a useful therapeutic option also for oligometastatic and oligorecurrent/oligoprogressive disease [16], rare histologies [17,18], or in combination with new drugs available for hormone-sensitive and castration-resistant PC. In recent years, advances in radiation planning and delivery techniques, in particular the advent of new-generation linac with the FFF mode, have improved treatment accuracy and given rise to the adoption of ultrahypofractionated radiation schedules in the form of SBRT [19] in different oncological settings, with acceptable toxicity [20][21][22][23][24][25]. Despite this, local failure after RT still remains a critical issue.…”

Can Radiotherapy Empower the Host Immune System to Counterattack Neoplastic Cells? A Systematic Review on Tumor Microenvironment Radiomodulation

“…This strategy impairs the capacity of neoplastic cells to counteract a new inflammatory/immunogenic response of the host immune system. Notwithstanding this, this strategy could have a point of concern since such a complex combination of IT to support RT priming could be associated with an increased risk of adverse events due to excessive deregulation of the host immune system, with the consequent specter of the autoimmunity risk [ 35 ].…”