Radiation and Dual Checkpoint Blockade Activate Non-Redundant Immune Mechanisms in Cancer

In this study, involving melanoma patients and a mouse model for melanoma, an optimal anti-tumour response was induced by using a combination of radiation with anti-CTLA4 and anti-PD-L1 antibody therapies, each attacking the tumour from a different angle. This study, involving melanoma patients and a mouse model for melanoma, demonstrates that an optimal anti-tumour response involves a combination of the three tested treatment modalities: high-dose radiation, together with two different types of immune checkpoint inhibitors (anti-CTLA4 and anti PD-L1), each attacking the tumour from a different angle. Immune checkpoint inhibitors1 result in impressive clinical responses2,3,4,5, but optimal results will require combination with each other6 and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.