Laurent Pierre-Antoine, Shi Liu, Bouarroudj Lisa, Benzazon Nathan, Gerbé De Thoré Marine, Liu Winchygn, Aglave Marine, Bergeron Paul, Naulin Flavie, Sitterlé Lisa, Morel Daphné, Levy Antonin, Clémenson Céline, Mondini Michele, Robert Charlotte, Meziani Lydia, Deutsch Eric
INSERM U1030 "Molecular Radiotherapy and Therapeutic Innovations", Gustave Roussy, Villejuif, France.
Department of Radiation Oncology, Gustave Roussy, Villejuif, France.
J Immunother Cancer. 2025 Jun 30;13(6):e011487. doi: 10.1136/jitc-2025-011487.
Low-dose radiotherapy (RT) is a promising treatment likely to increase the efficacy of immunotherapy, including programmed cell death ligand 1 (PD-L1) blockade, in cancer therapy. Further exploration and optimization of such combinatorial strategies are required. Notably, the ability of low-dose RT to enhance the efficacy of immune-checkpoint inhibitors (ICI) in distant, unirradiated tumors is debated. We used a stepwise preclinical approach in immunocompetent mice bearing different murine tumor models (MC38 or CT26), with one or two tumors per mouse. Mice received tumor-only irradiation consisting of either low-dose RT (2x0.5 Gy to 2x2 Gy) or high-dose RT (2x6 Gy to 2x8 Gy) combined with anti-PD-L1. Tumor growth rate and survival were compared across the different conditions. The immune microenvironments of both irradiated and distant unirradiated tumors were characterized using single-cell RNA sequencing. We first demonstrated that low-dose RT 2×2 Gy combined with anti-PD-L1 is as effective as high-dose RT 2×6 Gy in delaying the growth of irradiated tumors. Subsequently, we showed that low-dose RT to one tumor enhances the efficacy of anti-PD-L1 consolidation therapy in a distant, unirradiated tumor, thereby inducing an abscopal effect comparable to that observed with high-dose RT. Single-cell RNA sequencing analysis highlighted the polarization of tumor-associated macrophages (TAMs) within distant unirradiated tumors towards a pro-inflammatory phenotype following low-dose RT and anti-PD-L1. Depleting TAMs in distant unirradiated tumors using liposomal clodronate abrogated the abscopal effect driven by low-dose RT combined with anti-PD-L1. Our findings demonstrate the ability of low-dose RT to increase the efficacy of ICI in a distant tumor, resulting in a significant abscopal effect, and highlight the critical role of TAMs in the underlying mechanism, as well as a potential immune crosstalk between TAMs and activated lymphoid cells. These data propose low-dose RT as a potential strategy to improve the efficacy of immunotherapy in patients with metastatic solid tumors receiving anti-PD-L1.
低剂量放疗（RT）是一种很有前景的治疗方法，可能会提高免疫疗法（包括程序性细胞死亡配体1（PD-L1）阻断）在癌症治疗中的疗效。需要对这种联合策略进行进一步探索和优化。值得注意的是，低剂量RT增强远处未受照射肿瘤中免疫检查点抑制剂（ICI）疗效的能力存在争议。我们在患有不同小鼠肿瘤模型（MC38或CT26）的免疫活性小鼠中采用了逐步的临床前方法，每只小鼠有一个或两个肿瘤。小鼠接受仅针对肿瘤的照射，包括低剂量RT（2×0.5 Gy至2×2 Gy）或高剂量RT（2×6 Gy至2×8 Gy）联合抗PD-L1。比较不同条件下的肿瘤生长速率和生存率。使用单细胞RNA测序对受照射和远处未受照射肿瘤的免疫微环境进行表征。我们首先证明，低剂量RT 2×2 Gy联合抗PD-L1在延迟受照射肿瘤生长方面与高剂量RT 2×6 Gy一样有效。随后，我们表明对一个肿瘤进行低剂量RT可增强远处未受照射肿瘤中抗PD-L1巩固治疗的疗效，从而诱导出与高剂量RT相当的远隔效应。单细胞RNA测序分析突出了低剂量RT和抗PD-L1后远处未受照射肿瘤内肿瘤相关巨噬细胞（TAM）向促炎表型的极化。使用脂质体氯膦酸盐耗尽远处未受照射肿瘤中的TAM消除了低剂量RT联合抗PD-L1驱动的远隔效应。我们的研究结果证明了低剂量RT提高远处肿瘤中ICI疗效的能力，从而产生显著的远隔效应，并突出了TAM在潜在机制中的关键作用，以及TAM与活化淋巴细胞之间潜在的免疫串扰。这些数据提出低剂量RT作为一种潜在策略，以提高接受抗PD-L1治疗的转移性实体瘤患者免疫疗法的疗效。
