Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

Abstract

The effectiveness and side effects of radiotherapy (RT) are influenced by factors like dose and the volume of irradiated tissue. Low-dose RT (LDRT) enhances immune infiltration into tumors, while high-dose RT (HDRT) is more effective at killing cancer cells. We hypothesized that partial tumor irradiation (PI) combining the LDRT immunostimulatory effects with the HDRT cell-killing properties within the same tumor, alongside immunomodulators, could boost antitumor responses. In mouse colorectal and breast cancer models, PI combining LDRT (2Gy) and HDRT (16Gy) were delivered to different tumor regions with millimetric precision, significantly controlling tumor growth when paired with anti-PD1 therapy. Through flow cytometry, cytokine profiling, and single-cell RNA sequencing, we discovered that this approach reshapes CD8+ T cells into more cytotoxic, interferon-activated states but also increases pro-tumor neutrophils intratumor infiltration. Adding a CXCR2 antagonist to the treatment improved tumor control and survival. These findings suggest a potential strategy to reduce RT toxicity and enhance the efficacy of RT combined with immune checkpoint inhibitors.