Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses

Merkelcell.org Summary

Although carried out in mice, this study may have interesting implications for our patients. If radiation and immune therapy (such as Keytruda/pembrolizumab or Bavencio/avelumab) are to be given around the same time as radiation, this study suggests that radiation should be given before immune therapy is started. The simplest interpretation is that immune therapy causes the best anti-tumor T cells to enter the tumor, and if radiation is given shortly after that, these most effective T cells are killed on the battlefield. On the other hand, if radiation is given first, many tumor cells are killed and then the immune system comes in to clean up, with support of the immune stimulating drug.

Abstract

Although radiotherapy has been used for over a century to locally control tumor growth, alone it rarely induces an abscopal response or systemic antitumor immunity capable of inhibiting distal tumors outside of the irradiation field. Results from recent studies suggest that combining immune checkpoint blockades to radiotherapy may enhance abscopal activity. However, the treatment conditions and underlying immune mechanisms that consistently drive an abscopal response during radiation therapy combinations remain unknown. Here, we analyzed the antitumor responses at primary and distal tumor sites, demonstrating that the timing of αPD-1 antibody administration relative to radiotherapy determined the potency of the induced abscopal response. Blockade of the PD-1 pathway after local tumor irradiation resulted in the expansion of polyfunctional intratumoral CD8⁺ T cells, a decrease in intratumoral dysfunctional CD8⁺ T cells, expansion of reprogrammable CD8⁺ T cells, and induction of potent abscopal responses. However, administration of αPD-1 before irradiation almost completely abrogated systemic immunity, which associated with increased radiosensitivity and death of CD8⁺ T cells. The subsequent reduction of polyfunctional effector CD8⁺ T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses. Therefore, this report maximizes the potential synergy between radiotherapy and αPD-1 immunotherapy, information that will benefit clinical combinations of radiotherapy and immune checkpoint blockade.