Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Nature
Christina Twyman-Saint VictorAndy J Minn

Abstract

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other 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/Tre...Continue Reading

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Methods Mentioned

BETA
biopsies
biopsy
flow cytometry
surgical

Clinical Trials Mentioned

NCT01497808

Software Mentioned

FlowCore R package
Bioconductor
randomForestSRCM
mogene10sttranscriptcluster
PERCIST
TreeStar
mogene20sttranscriptcluster
GSA ” R package
FlowJo
R environment for statistical computing

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