Radiation improved IL-21 cancer immunotherapy

Abstract Interleukin-21 is a pleiotropic cytokine which has shown promising antitumor activities in several preclinical models but the response rate in phase I–II clinical studies has been disappointing. Therefore, the optimal usage of IL-21 as an effective therapy against cancers remains to be studied. Radiotherapy, a well establish treatment modality for cancers, has shown its potential in immunogenic modulation by stimulating immune cell phagocytosis and inducing local tumor-associated antigens releasing. We hypothesize that a synergistic antitumor effect could be achieved by combining IL-21 with radiation through releasing neoantigens and amplifying adaptive antitumor immune responses against both primary and metastatic tumors. We treated mice bearing large established tumors with radiation, IL-21 or a combination of radiation and IL-21. Mice treated with radiation alone showed delayed tumor growth, while IL-21 treatment had very little effect. In contrast, a synergistic antitumor effect was achieved in the combination group, which not only led to complete tumor regression of primary tumors, but also significantly suppressed the growth of distant, untreated metastatic tumors. Mechanistic analysis revealed that combination therapy increased accumulation of tumor-infiltrating CD8+ T cells which showed enhanced functional activities, marked by increased expression of CD107a, IFN-γ and TNF-α. Moreover, mice that had been cured by the combination therapy developed memory responses against the subsequent tumor re-challenge. Our results demonstrate that combination of IL-21 and radiation has potent antitumor activity against both primary and metastatic tumors and could open a new perspective for cancer therapy.