Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models

Abstract

Abstract Hydrogen peroxide (H 2 O 2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H 2 O 2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H 2 O 2 on antitumor immunity remain unclear. To investigate the effects of H 2 O 2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H 2 O 2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H 2 O 2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H 2 O 2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor‐draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H 2 O 2 /RT combination group. In addition, analyses of tumor‐infiltrating lymphocytes showed that the number of CD8 + (cluster of differentiation 8) T cells and the frequency of IFN‐γ + (interferon gamma) CD8 + T cells were higher in the noninjected/nonirradiated tumors in the H 2 O 2 /RT group compared to those in the other groups. PD‐1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H 2 O 2 /RT group. Intratumoral injection of H 2 O 2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD‐1 blockade. These findings promote the development of H 2 O 2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.