Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand Rae1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide and immune checkpoint blockade to patients with immune desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low-T cell infiltrated tumors.
Herrera, F. G., Ronet, C., Ochoa de Olza, M., Barras, D., Crespo, I., Andreatta, M., … Coukos, G. (2021). Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy. Cancer Discovery, candisc.0003.2021. https://doi.org/10.1158/2159-8290.cd-21-0003