Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

Abstract

Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.

Keywords: DNA damage; abscopal effect; antitumor immunity; immunotherapy; ionizing radiation; tumor microenvironment.

Figure 1:. Radiation-induced secretion of IFN-I is critical for abscopal responses.

Ionizing radiation leads to the release of tumor associated antigens (TAA) and damaged DNA that can stimulate the production of type-I interferon via the cGAS/STING pathway in tumor cells. The subsequent secretion of IFN-I and interferon-stimulated genes (including CXCL10) promote the recruitment and activation of BATF3-DCs. Once in the tumor, BATF3-DCs take up the TAA and tumor-derived DNA to further stimulate the production of IFN-I. Activated BATF3-DCs then migrate to the tumor draining lymph node where they can prime CD8+ T cells to initiate cytotoxic T-cell responses. Once activated, cytotoxic T lymphocytes (CTLs) migrate to the irradiated tumor and eliminate residual cancer cells, and to distant metastatic sites leading to systemic tumor regression (abscopal effect).

Figure I:

A- Direct effect. Following X-ray, an electron is ejected and directly damages DNA. B- Indirect effect. The incident photon ejects an electron, which creates a free radical. The diffusing free radical then causes damage to DNA.

Figure II:

Major type of DBS breaks. Simple DSBs involve two broken DNA ends (i.e. two-ended DSB) in close proximity. Complex DSBs consist in two broken DNA ends in proximity to additional DNA damage (i.e., cross-links, single stranded breaks, etc...) or a DSB within a replication fork (one-ended DSB).