Radiation as an immunological adjuvant: current evidence on dose and fractionation

Abstract

Ionizing radiation to a cancer site has the ability to convert the irradiated tumor in an immunogenic hub. However, radiation is a complex modifier of the tumor microenvironment and, by itself, is seldom sufficient to induce a therapeutically significant anti-tumor immune response, since it can also activate immune suppressive pathways. While several combinations of local radiation and immunotherapy have been shown in pre-clinical models to induce powerful anti-tumor immunity, the optimal strategy to achieve this effect remains to be defined. When used in vivo, radiation effects on tumors depend on the dose per fraction applied, the number of fractions used, and the total dose. Moreover, the interplay of these three variables is contingent upon the tumor setting studied, both in pre-clinical and clinical applications. To enable repair of the collateral damage to the normal tissue, radiation is usually given in multiple fractions, usually of 2 Gy. Generally, the use of larger fractions is limited to stereotactic applications, whereby optimal immobilization reduces inter- and intrafraction movement and permits a very conformal delivery of dose to the target, with optimal exclusion of normal tissue. Translation of the partnership of radiation and immunotherapy to the clinic requires a careful consideration of the radiation regimens used. To date, little is known on whether different dose/fractionation regimens have a specific impact on the anti-tumor immune response. Most experiments combining the two modalities were conducted with single fractions of radiotherapy. However, there is at least some evidencethat when combined with some specific immunotherapy approaches, the ability of radiation to promote anti-tumor immunity is dependent on the dose and fractionation employed. We critically review the available in vitro and in vivo data on this subject and discuss the potential impact of fractionation on the ability of radiation to synergize with immunotherapy.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…38 Meanwhile, it is well acknowledged that anti-tumor immune mechanisms can be stimulated by radiotherapy in the sense of an in situ cancer vaccination. 4,6 However, the optimal dosing and fractionation regimen for the induction of anti-tumor immunity by ionizing irradiation remain controversial. 21,39–41 …”

“…HCC1937 cells were seeded onto sterile cover slips into 24-well plates (4x10 4 cells per well) and incubated for adherence overnight. On the next day, HCC1937 cells were irradiated at the indicated doses and fixed on day 1 and 4 after irradiation for 10 min with an isotonic solution of 3.7% formaldehyde (Merck Millipore, Darmstadt, Germany) and 0.1% Triton X-100 (Sigma-Aldrich).…”

“…1 However, meanwhile it is well accepted that immune mechanisms contribute to the therapeutic outcome and that the mode of tumor cell death determines if and to which extent irradiation converts the tumor into an in situ vaccine. 2–4 Apart from tumor antigens which need to be made accessible to the immune system, the presence of adjuvants orchestrating the recruitment, differentiation, and activation of antigen-presenting cells (APCs) in the tumor microenvironment is of pivotal importance for the successful priming of anti-tumor immunity. 5,6 In this regard, tumor cells undergoing immunogenic forms of cell death are known to release damage-associated molecular patterns (DAMPs), including heat shock protein 70 (HSP70), high mobility group box1 (HMGB1), and ATP, thereby supporting the recruitment and maturation of APCs.…”

The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade

“…Despite substantial improvements in image-guided stereotactic body radiation therapy (SBRT), which permits the delivery of larger doses of RT over a much shorter time period (hypofractionation), and in the administration of a single large ablative dose, the majority of RT in the clinic is delivered in multiple daily fractions of approximately 1.8-2 Gy. However, relatively few studies have addressed the immunogenicity of fractionated RT with this lower dose (reviewed in 5 ), therefore this was the focus of our study.…”

Peripheral myeloid-derived suppressor and t-regulatory pd-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients

“…Through an active humoral and physical cross talk ME can determine invasion, ability to metastasize, immunogenicity of cancer and response to anticancer therapies including radiation therapy (RT). The effects of radiotherapy reported on tumor cells are conflicting, and the general belief on immunity is that different microenvironments and diverse delivery modalities may induce activation or inhibition of immune response and the size of fraction is one of the variables involved in such a dualism [1][2][3].…”