Radiotherapy, Lymphopenia, and Host Immune Capacity in Glioblastoma: A Potentially Actionable Toxicity Associated with Reduced Efficacy of Radiotherapy

Radiotherapy is cytotoxic to tumor cells and is therefore a critical component of therapy for many malignancies, including glioblastoma (GBM). We now appreciate the value of the immunomodulatory effects of radiation that may be important to overall therapeutic success in some patients with this primary brain tumor. Although potentially beneficial immune-stimulating properties of radiotherapy treatment have been the focus of recent study, this modality is actually at the same time associated with the depletion of lymphocytes, which are crucial to the defense against neoplastic development and progression. In this review, we describe the association of systemic lymphopenia with poor tumor outcome, present evidence that radiotherapy is an important contributing cause of lymphodepletion, describe the systemic immune context of tumor and brain injury that contributes to immunosuppression, describe other contributing factors to lymphopenia including concomitant medications and treatments, and speculate about the role of the normal physiologic response to brain injury in the immunosuppressive dynamics of GBM. Radiotherapy is one significant and potentially actionable iatrogenic suppressor of immune response that may be limiting the success of therapy in GBM and other tumor types. Altered strategies for radiotherapy more permissive of a vigorous antineoplastic immune response may improve outcome for malignancy.