The abscopal effect: a sense of DNA damage is in the air
Timothy P. Lippert, Roger A. Greenberg
Timothy P. Lippert, Roger A. Greenberg
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e148274. https://doi.org/10.1172/JCI148274.
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The abscopal effect: a sense of DNA damage is in the air

Abstract

Tumor metastasis is a singularly important determinant of survival in most cancers. Historically, radiation therapy (RT) directed at a primary tumor mass was associated infrequently with remission of metastasis outside the field of irradiation. This away-from-target or “abscopal effect” received fringe attention because of its rarity. With the advent of immunotherapy, there are now increasing reports of abscopal effects upon RT in combination with immune checkpoint inhibition. This sparked investigation into underlying mechanisms and clinical trials aimed at enhancement of this effect. While these studies clearly attribute the abscopal effect to an antitumor immune response, the initial molecular triggers for its onset and specificity remain enigmatic. Here, we propose that DNA damage–induced inflammation coupled with neoantigen generation is essential during this intriguing phenomenon of systemic tumor regression and discuss the implications of this model for treatment aimed at triggering the abscopal effect in metastatic cancer.

Authors

Timothy P. Lippert, Roger A. Greenberg

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Figure 3

Mechanisms of neoantigen generation upon DNA damage.

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Mechanisms of neoantigen generation upon DNA damage. Damaged DNA may be ...
Damaged DNA may be intergenic, or between genes and promoter sequences. Damaged DNA may be repaired by end-joining pathways upon pharmacological impairment or HR deficiency (left pathway). Such repair is associated with sequence changes due to the fact that Alt-EJ and MMR result in small indels at the site of repair. In addition to this, repair by NHEJ involves end processing by factors such as Artemis, and this also results in small sequence changes at the site of ligation. Together, such repair mechanisms result in changes in nucleotide sequence at the site of repair. The resulting missense mutations are capable of producing changes in amino acid sequence that may give rise to neoantigen. In a complementary or alternative mechanism, breakage of DNA at two distinct loci may give rise to promoter translocation and aberrant overexpression of a given antigen (right pathway). These pathways are likely not exclusive events and may give rise to tumor neoantigens targeted by the immune system during the abscopal effect.