Abstract
We previously reported that a combination of 10 Gy of X-ray irradiation and dual immune checkpoint blockade with anti-CTLA-4 (C4) and anti-PD-L1 antibodies produced a significant shrinkage of irradiated and unirradiated tumors (abscopal effect) and prolonged overall survival. However, the optimal radiation delivery regimen combined with single immune checkpoint blockade of C4 for inducing a maximum systemic antitumor response still remains unclear, particularly for patients with osteosarcoma. We used syngeneic C3H mice that were subcutaneously injected with LM8 osteosarcoma cells into both legs. C4 was administered three times, and one side of the tumor was irradiated by X-ray beams. The optimal radiation dose required to induce the abscopal effect was explored with a focus on the induction of the type-I interferon pathway. Radiation delivered in a single fraction of 10 Gy, 4.5 Gy × 3 fractions (fx), and 2 Gy × 8 fx with C4 failed to produce significant inhibition of unirradiated tumor growth compared with monotherapy with C4. Dose escalation to 16 Gy in a single fraction, or the equivalent hypofractionated dose of 8 Gy × 3 fx, which significantly increased secretion of IFN-β in vitro, produced a dramatic regression of both irradiated and unirradiated tumors and prolonged overall survival in combination with C4. Furthermore, irradiation at 16 Gy in both a single fraction and 8 Gy × 3 fx diminished regulatory T cells in the unirradiated tumor microenvironment. These results suggest that total dose escalation of radiation is crucial in C4 therapy to enhance the antitumor response in both local and distant tumors and prolonged overall survival regardless of fractionation for osteosarcoma.
Highlights
Radiotherapy (RT) has been a component of the standard treatment against many types of solid tumors and is highly effective for local control
Since the C4 treatment with a single fraction of 10 Gy and the equivalent fractionated doses showed no significant reduction in the IR and UnIR tumors or extension of overall survival compared with the C4 only group, we examined whether further dose escalation increased the antitumor immunity
To the best of our knowledge, this is the therapeutic response of osteosarcoma to single immune checkpoint blockade combined the first evidence that delivery revealedregimens the necessity of radiation escalation regardless of the number with various radiation remained unclear.dose
Summary
Radiotherapy (RT) has been a component of the standard treatment against many types of solid tumors and is highly effective for local control. It has been widely reported that tumor regression is observed, even in distant tumors out of the radiation field, when RT is utilized for patients with multiple metastasis [1,2,3,4]. This phenomenon is an immune-mediated event known as the abscopal effect [5,6,7,8,9,10]. Together with the radiation-induced abscopal effect, combined therapy with immune checkpoint blockade has been found to be an effective strategy for some cancers [17,18,19,20,21,22,23], the optimal combination strategy, especially in the context of radiation delivery (e.g., sequence, total dose, and fractionation) remains unclear for some types of tumors
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