The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

Abstract

Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal effect. However, the occurrence of systemic anti-tumor effects was deemed too rare and unpredictable to be a therapeutic goal. Recent studies suggest that immunotherapy and radiation in combination may enhance the abscopal response. Increasing numbers of cases are being reported since the routine implementation of immune checkpoint inhibitors, showing that combined radiotherapy with immunotherapy has a synergistic effect on both local and distant (i.e., unirradiated) tumors. In this review, we summarize pre-clinical and clinical reports, with a specific focus on the mechanisms behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy.

Keywords: abscopal effect; checkpoint blockade; radiotherapy.

Figure 1

Proportion of patients presenting with upfront distant disease by cancer type in the period 2010–2016.

Figure 2

Pre-treated tumor with exhausted CD8⁺ T cells and tumor proliferating without immune inhibition. Radiation of tumors leads to double-stranded DNA breaks and downstream cGAS-STING signaling, which in turn increases Type 1 IFN release. Immunogenic cell death releases DAMPs such as HMGB1, HSP, GP96, and calreticulin. HMGB1 activates Dendritic Cells through TLR4-dependent pathway. Anti-CTLA-4 agents act on naïve and regulatory T cells while anti-PD-1 agents predominantly work on exhausted T cells.