In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [¹⁷⁷Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [¹⁷⁷Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2–positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [¹⁷⁷Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [¹⁷⁷Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs’ subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [¹⁷⁷Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [¹⁷⁷Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [¹⁷⁷Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to ¹⁷⁷Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis. Visual Abstract

Radiation therapy (RT) is known for its ability to kill cancer cells in an immunogenic manner. Recent preclinical data demonstrate that targeted alpha-particle therapy shares with RT the capacity to elicit immunostimulatory effects, standing out as a promising strategy to circumvent immune checkpoint inhibitor resistance in immunologically ‘cold’ tumors.

Preclinical and clinical studies increasingly show that the immune response plays a major role in radiotherapy. Here, we investigated the role of major histocompatibility complex class I (MHC-I) molecules recognized by cytotoxic CD8⁺ T cells in the response to radiopharmaceutical therapy (RPT). Methods: Two murine melanoma cell lines that express low and high MHC-I levels (B16F10 and B16K1, respectively) were grafted in syngeneic or athymic and nude mice, and the response to a single injection of [²²⁵Ac]Ac-DOTA-TA99 monoclonal antibodies (9.25 or 18.5 kBq) was assessed and related to dosimetry. For clinical relevance, MHC-I expression was determined in samples from patients with well-differentiated, iodine-avid metastatic thyroid cancer and well-differentiated grade 2 mid-gut neuroendocrine tumors. Results: RPT efficacy was enhanced by T-cell presence and MHC-I expression. In mice harboring B16F10 and B16K1 melanoma tumors, RPT showed a stronger antitumor effect in C57BL/6J (immunocompetent) animals than in athymic and nude (immunodeficient) animals, suggesting a crucial role of T-cell–mediated immune responses. Moreover, the response to irradiation was the same in B16K1 MHC-I_high tumors with a low absorbed dose of α-RPT and in B16F10 MHC-I_low tumors with a 4 times higher absorbed dose. These results indicate that CD8⁺ T cells can counterbalance low tumor irradiation. Conversely, delivering high absorbed doses leads to side effects and seems to prevent immune system activation, thereby not taking advantage of these mechanisms. Our results also indicate that MHC-I can be used as a predictive biomarker of RPT response in lesions receiving low absorbed doses and that RPT treatment regimens should be reconsidered in the function of the MHC-I expression level. Conclusion: This study shows that MHC-I expression can predict RPT immunostimulatory effects. This is relevant in metastatic disease where lesions in the same patient can receive very low or very high absorbed doses. Visual Abstract