Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer

Abstract

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies

“…Recent studies have indicated that FLASH-RT and CONV-RT might prime different immune responses in tumors, and better tumor control efficiency might be achieved due to increased recruitment of T lymphocytes. This has promoted research interest in combining FLASH-RT with immunotherapy to further enhance the therapeutic efficiency [17] . To further investigate the immunomodulation of FLASH-RT or CONV-RT, flow cytometry and IHC staining were performed to determine the immune response in tumor samples.…”

“…However, regulatory T cells (T reg ), an important subset of CD4 + T cells, have immunosuppressive effects in tumors [30] , T reg can evade tumor-specific immune responses [31] . Eggold et al [17] reported that both electron CONV-RT and FLASH-RT could reduce regulatory T cells and increase cytolytic CD8 + T cells in the ovarian cancer TME 17 days PI, and that CD8 + T cell infiltration could be enhanced by a combination of αPD-1 treatment 12 or 17 days PI. In our study, CD8 + T cell infiltration was significantly increased in Py8119 xenograft tumor 2 weeks after both FLASH-RT and CONV-RT.…”

“…This unique biological response drives research enthusiasm in the clinical applications of FLASH-RT [10] , [13] . Although the underlying mechanisms of the FLASH effect are unclear, attempts are ongoing to define the involved affecting factors and [3] , [14] , [15] , identify the triggering conditions of the FLASH effect to take advantage of the unique radiobiological response [8] , [16] , and enlarge the therapeutic window by incorporating other therapy techniques [17] .…”

“…Kim et al found that FLASH-RT increased CD8 + T cell infiltration 6 h post-RT, activated myosin light chains, and altered the TME by increasing infiltration of S100A8 + myeloid and CD8α + cytotoxic T cells in a Lewis lung carcinoma model [14] . It was hypothesized that FLASH-RT combined with immune checkpoint inhibitors might enhance the therapeutic efficacy of FLASH-RT [17] . Eggold et al reported that FLASH-RT increased intratumoral CD8 + T cell infiltration in combination with programmed death-1 (PD-1) immune checkpoint inhibition treatment in both anti-PD-1 antibody (αPD-1)-resistant ID8 model and αPD-1-sensitive UPK10 model of ovarian cancer 17 and 12 days post-RT, respectively [17] .…”

“…It was hypothesized that FLASH-RT combined with immune checkpoint inhibitors might enhance the therapeutic efficacy of FLASH-RT [17] . Eggold et al reported that FLASH-RT increased intratumoral CD8 + T cell infiltration in combination with programmed death-1 (PD-1) immune checkpoint inhibition treatment in both anti-PD-1 antibody (αPD-1)-resistant ID8 model and αPD-1-sensitive UPK10 model of ovarian cancer 17 and 12 days post-RT, respectively [17] .…”