PD-1 Restrains Radiotherapy-Induced Abscopal Effect

Abstract

We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABRinduced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1-blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11a high CD8 þ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumorspecific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer.

An Abscopal Response to Radiation Therapy in a Patient with Metastatic Non-Small Cell Lung Cancer: A Case Report

“…Immune checkpoint inhibitors can strengthen the antitumor immune function caused by radiotherapy, especially as the latter increases the expression of PD-L1 on tumor cells [19]. In fact, combined blockade of PD-1 and CTLA-4 during radiotherapy demonstrated a significant therapeutic effect in both irradiated and non-irradiated large-burden tumors in vivo [20]. However, the possibility that ipilimumab alone might have been responsible for the aforementioned patient's response cannot be ruled out.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…94 However, the abscopal effect is rare to occur in patients with metastatic cancer, possibly because of inappropriate fractionation dose or blockade of antitumor response that is supposed to be triggered by radiotherapy. 95 Thus, an optimal combination to maximize the abscopal effect is urgently needed. In terms of NSCLC, combining PD-1/PD-L1 antibodies rather than CTLA-4 antagonists with radiotherapy are more feasible to induce the abscopal effect.…”

“…Preclinical studies confirmed that upregulation of PD-1 limited the radiotherapy-induced abscopal effect and PD-1 blockade effectively potentiated the immune response. 95 Recently, a phase II study was ongoing to evaluate the combination of nivolumab and radiosurgery in cancer patients, including renal cell carcinoma and NSCLC, with brain metastases. The patients involved in the trial are planned to receive nivolumab 240 mg (q2w) intravenously and radiosurgery with customized dose from 15 to 20 Gy will be delivered after the first dose of nivolumab (NCT02978404).…”

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

“…The combination of local radiotherapy and immunemodulation can augment local tumor control and cause distant antitumor effects (abscopal), increasing tumor-antigen release and antigen-presenting cell (APC) cross-presentation, improving dendritic cell (DC) function, and enhancing T cell priming (110)(111)(112)(113) (Figure 2). On the other hand, ionizing radiation can also generate chemotactic signals that recruit several myeloid-cell types with distinct roles in T cell suppression (114)(115)(116).…”