Radiation-induced effects and the immune system in cancer

Abstract

Chemotherapy and radiation therapy (RT) are standard therapeutic modalities for patients with cancers, and could induce various tumor cell death modalities, releasing tumor-derived antigens as well as danger signals that could either be captured for triggering anti-tumor immune response. Historic studies examining tissue and cellular responses to RT have predominantly focused on damage caused to proliferating malignant cells leading to their death. However, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, particularly with respect to effects on immune cells and infiltrating tumors. This review will focus on immunologic consequences of RT and discuss the therapeutic reprogramming of immune responses in tumors and how it regulates efficacy and durability to RT.

Keywords: cancer; cell death; immune response; low-dose radiotherapy; radiation therapy; tumor microenvironment.

FIGURE 1

Schematic representation of working hypothesis for RT-induced anti-tumor immune regulation. (1) Within the primary tumor microenvironment (blue area) untreated tumors express few exposed tumor-associated antigens (TAAs). (2) Exposure to RT induces the (3) dying tumors to express significantly more TAAs on their surface and to release DAMPS, (4) which are both taken up by professional APCs resulting in their activation. Activation of APC is greatly enhanced (+) by the presence of Th1-type cytokines and significantly suppressed (−) by the presence of Th2-type cytokine. (5) Activated APCs migrate to draining lymph nodes (DLN; gray area). (6) Within the DLN, T cell exposure to APC is achieved by direct contact with activated APCs. (7) Activated T cells increase in size and granularity. (8) The activated T cells migrate from the DLN as tumor-specific T cells (CD8⁺ CTL) into the tumor microenvironment. (9) Within the tumor microenvironment CD8⁺ CTL perform tumor-specific killing.