The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

Abstract

Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease.

Keywords: fibrosis; lung; lymphocytes; pneumonitis; radiotherapy.

Figure 1

Schematic representation showing the phases of radiation-induced lung injury over time with a view on the dual role of lymphocytes during radiation-induced pneumopathy. Damage to the lung results in an initial response (acute radiation response) due to DNA damage, ROS induction, and apoptosis. Release of damage-associated molecular patterns (DAMPs) and secretion of cytokines and chemokines activate the immune system. This phase passes over into an acute inflammatory phase (pneumonitis) that is characterized by an enhanced pro-inflammatory response and vascular leakage. In this phase, diverse lymphocyte subpopulations like T_H1, T_H17, and potentially innate lymphoid cells (ILC) can contribute to inflammation, whereas it is believed that the lymphocyte subpopulations T_reg are needed to control harmful, excessive pro-inflammatory responses. Resolution of inflammation and repair induction is paralleled by late mitotic cell death subsequent, hypoxia, release of DAMP, cytokines, and growth factors. These alterations in the lung micromilieu are described for the chronic phase of radiation-induced pneumopathy. These environmental changes can contribute to immunomodulation; here, it is believed that lymphocytes (T_H2, T_H9, T_reg, and potentially ILC) show an anti-inflammatory or even pro-fibrotic phenotype, thereby having the potential to further alter the environment in the lung toward the induction of disease-promoting myofibroblasts and fibrosis development.

Figure 2

How the microenvironment shapes the immune response and vice versa. We hypothesize that radiation induces damage to tissue resident cells, e.g., endothelial and epithelial lung cells, mesenchymal stem cells (MSC) as well as in resident immune cells. The resulting tissue damage can initiate stress responses or cell death with subsequent release of cytokines/chemokines and damage-associated molecular patterns (DAMPs). This initial damage response leads to the recruitment and activation of diverse immune cells to the lung, among them lymphocytes. Further activation, proliferation of these cells, and secretion of cytokines shape the pulmonary micromilieu toward inflammation and—if this response is too excessive—to the development of severe pneumonitis. Late chronic mitotic cell death and subsequent tissue hypoxia lead to the release of DAMPs and cytokines/chemokines from resident cells thereby altering the micromilieu in the lung. These environmental changes impact on the immune cells present in the lung tissue and promote an altered cytokine release of immune cells. Finally, epithelial-mesenchymal-transition, endothelial-mesenchymal-transition, mesenchymal stem cell differentiation, and the altered environment contribute to the induction of activated myofibroblasts, collagen deposition, and fibrosis.