Radiation-induced immune response in novel radiotherapy approaches FLASH and spatially fractionated radiotherapies

Radiation therapy is currently undergoing a paradigm shift, sparked by the increasing evidence of the importance of the so-called non-targeted effects (Asur et al., 2012, Asur et al., 2015). These non-targeted effects include bystander effects as well as stromal and immunological changes (De Martino et al., 2021; Lumniczky et al., 2017; Yoshimoto et al., 2015). Among these three non-targeted effects, the immunomodulatory effects of radiation therapy (RT) reshape tumor microenvironments (TME) (Donlon et al., 2021). Radiotherapy can have an immunosuppressive or immunostimulatory effect on irradiated tumors. The nature of these two effects would depend on the immune context of cancer and the total dose, dose per fraction, and treatment length. However, radiobiologists have not yet elucidated the optimal effective doses and fractionation for immune priming (Boustani et al., 2019; Colton et al., 2020; De Martino et al., 2021; Demaria et al., 2021; Demaria and Formenti, 2012). Standard RT in conventional fractionation schemes delivers 2 Gy per fraction, with 1 fraction a day, five times a week over the course of 5–7 weeks, in a homogeneous and wide field. This fractionation scheme is the “gold standard” and is still widely used in clinic. Standard RT was historically contemplated as an immunosuppressive treatment. This consideration was based on different aspects, such as total body irradiation to prepare patients for allogenic transplant (Boustani et al., 2019) or the increased lymphopenia observed in patients as a number of the fractions delivered (Nordman and Toivanen, 1978; Wang et al., 2020; Wasserman et al., 1989).

Recent preclinical evidence indicated that RT reshapes the tumor microenvironment (TME) (Donlon et al., 2021). The tumor microenvironment is a complex and dynamic environment. The TME comprises several actors, such as blood vessels, cancer-associated fibroblasts, and immune cells. Among immune cells, T cells, B cells, Natural Killers (NK), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are of particular interest. Cancer cells develop mechanisms to escape the immune surveillance, leading to an immunosuppressive TME. The interaction between the TME and irradiation is complex and depends on the degree of immunosuppression within the TME, the radiosensitivity of the different immune cell populations (lymphocytes are known to be more radiosensitive than myeloid cells due to their proliferative state (Cytlak et al., 2022)), as well as the degree of hypoxia (Song et al., 2022). The abovementioned factors shift the radiation-induced response toward a greater immune activation or suppression (Cytlak et al., 2022; Rodríguez-Ruiz et al., 2018). Moreover, the local immune-mediated antitumor response depends on the dose, fractionation scheme, and dose delivery method (Boustani et al., 2019; Demaria et al., 2021).

The immune-mediated effects of RT include detecting the release of tumoral neoantigens, immunogenic cell death, and detecting the damages-associated molecular pattern (DAMPs). DAMPs initiate tumoral neoantigen processing by dendritic cells and other antigen-presenting cells (APC). The dendritic cells prime and activate effector T cells against the tumor. During radiation-induced cell death, dying cancer cells accumulate double-stranded DNA and RNA breaks in their cytosol sensed by the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway. The cGAS/STING pathway initiates an inflammatory and immune response. The release of reactive oxygen species (ROS) following radiation attracts and activates the innate immune system, notably neutrophils and NK. The effects of RT are propagated by cytokines and chemokines on a tissue and tumor-dependent basis (Cytlak et al., 2022). All its signaling pathways activate the innate and adaptive immune system against the tumor (Craig et al., 2021).

Conventional fractionation schemes are not usually effective in eliciting an immune response (Boustani et al., 2019; Turgeon et al., 2019). Hypofractionation regimens deliver a dose per fraction between 6 and 20 Gy (Barillot et al., 2018; Brown et al., 2014; Potters et al., 2010; Vallard et al., 2020). Small animal experiments suggest that these regimens induce immunogenic cell death and subsequent immune cell infiltration (Dewan et al., 2009; Ngwa et al., 2018). Whether this is the most effective dose range per fraction in humans remains to be determined. Moreover, T cell infiltration into the tumors usually peaks at 5–8 days after irradiation (Dovedi et al., 2017; Frey et al., 2017). In the case of prolonged fractionation schemes, irradiation at those time points could be unfavorable. However, T cell infiltration and abscopal effect do not seem to be impacted by the length of the treatment in the case of hypofractionation in a mice melanoma model (Zhang and Niedermann, 2018). Furthermore, tumor-infiltrating T cells survived either fractionated RT or single high doses and produced more IFN-γ than non-irradiated T cells (Arina et al., 2019).

FLASH radiation therapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are novel radiation therapy techniques recently developed. The distinct dose delivery methods of FLASH-RT (Favaudon et al., 2014; Zhang et al., 2021) and SFRT (Prezado, 2022) could lead to a different immune modulation than conventional RT.

FLASH-RT is characterized by ultra-high dose rates (UHDR) (≥40 Gy/s) and very short delivery times (<200 ms) employed (Bourhis et al., 2019a; Favaudon et al., 2014; Griffin et al., 2020; Wilson et al., 2020). Spatially fractionated radiation therapy (SFRT) spatially modulates the dose with alternating regions of high dose, called peaks, and low dose, called valleys (De Marzi et al., 2019; Prezado, 2022; Yan et al., 2020). Four main types of SFRT can be distinguished: GRID-RT (Mohiuddin et al., 1999), lattice RT (LRT) (Amendola et al., 2019), minibeam RT (MBRT) (Dilmanian et al., 2006), and microbeam RT (MRT) (Slatkin et al., 1992). While the first two use centimeter-sizes beams, the last two work with beams in the range of hundreds and tens of micrometers, respectively. Usually, the beamlets are separated by two to four times the size of the beamlet, so the percentage of high dose region vs. low dose region is similar in the four technics. It's to keep in mind that GRID-RT and LRT differ from MBRT and MRT in the size of beamlets which impacts the dose used in the different technics. When GRID-RT and LRT use doses from 10 to 20 Gy in the peaks, MBRT, and MRT can reach hundreds of grays in the peaks. Further details on the individual techniques can be found elsewhere (Prezado, 2022) (Fig. 1). Moreover, GRID-RT and LRT are currently used in clinics, whereas MBRT and MRT are in the preclinical stage. Review of clinical studies on GRID-RT and LRT can be found elsewhere (Billena and Khan, 2019; Wu et al., 2020). GRID-RT is usually used for debulking large tumors before concomitant conventional radiotherapy with chemotherapy. GRID-RT alone is used in palliative care (Prezado, 2022). LRT is used for late-stage bulky tumor and metastases treatment (Jiang et al., 2021; Prezado, 2022).

FLASH-RT and SFRT remarkably reduced healthy tissue toxicities (Favaudon et al., 2014; Lamirault et al., 2020; Montay-Gruel et al., 2017, Montay-Gruel et al., 2019, Montay-Gruel et al., 2020; Prezado, 2022; Prezado et al., 2017; Vozenin et al., 2019a) while maintaining and sometimes increasing tumor control (Amendola et al., 2019; Billena and Khan, 2019; Favaudon et al., 2014; Kim et al., 2021a; Mohiuddin et al., 2020; Montay-Gruel et al., 2021; Prezado et al., 2019). In addition, both FLASH-RT and SFRT have been shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. Several hypotheses on radiobiological mechanisms involved in the response of FLASH-RT have been proposed. These mechanisms include a transient oxygen depletion resulting from radiolytic oxygen consumption, differential activation of metabolic and detoxification pathways between normal and tumor cells in response to reactive oxygen and nitrogen species, or radical-radical recombination (Friedl et al., 2022). Additionally, FLASH-RT has been hypothesized to impact differentially circulating immune cells, tumor immune microenvironment, cytokine production, and inflammatory responses (Zhang et al., 2021). Concerning SFRT, the main radiobiological mechanisms described in the literature are differential vascular effects (Bouchet et al., 2015), cell signaling effects (bystander-like, cohort effects) (Asur et al., 2012, Asur et al., 2015), inflammation and immunomodulatory effects (Bazyar et al., 2021), including abscopal effect, and cell migration (Dilmanian et al., 2002). More details on both FLASH and SFRT techniques, in technical and radiobiological aspects, can be found in Prezado (2022).

Novel RT modalities might have a distinct impact on the immune system, although hypothetically based on different biological mechanisms. This review will examine the current knowledge of immune responses after FLASH-RT or SFRT.

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