Cisplatin Facilitates Radiation-Induced Abscopal Effects in Conjunction with PD-1 Checkpoint Blockade Through CXCR3/CXCL10-Mediated T-cell Recruitment

Abstract

Purpose: Localized radiotherapy can cause T-cell-mediated abscopal effects on nonirradiated metastases, particularly in combination with immune checkpoint blockade (ICB). However, results of prospective clinical trials have not met the expectations. We therefore investigated whether additional chemotherapy can enhance radiotherapy-induced abscopal effects in conjunction with ICB.

Experimental design: In three different two-tumor mouse models, triple therapy with radiotherapy, anti-PD-1, and cisplatin (one of the most widely used antineoplastic agents) was compared with double or single therapies.

Results: In these mouse models, the response of the nonirradiated tumor and the survival of the mice were much better upon triple therapy than upon radiotherapy + anti-PD-1 or cisplatin + anti-PD-1 or the monotherapies; complete regression of the nonirradiated tumor was usually only observed in triple-treated mice. Mechanistically, the enhanced abscopal effect required CD8⁺T cells and relied on the CXCR3/CXCL10 axis. Moreover, CXCL10 was found to be directly induced by cisplatin in the tumor cells. Furthermore, cisplatin-induced CD8⁺T cells and direct cytoreductive effects of cisplatin also seem to contribute to the enhanced systemic effect. Finally, the results show that the abscopal effect is not precluded by the observed transient radiotherapy-induced lymphopenia.

Conclusions: This is the first report showing that chemotherapy can enhance radiotherapy-induced abscopal effects in conjunction with ICB. This even applies to cisplatin, which is not classically immunogenic. Whereas previous studies have focused on how to effectively induce tumor-specific T cells, this study highlights that successful attraction of the induced T cells to nonirradiated tumors is also crucial for potent abscopal effects.