Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy

Lewis Zhichang Shi, Tihui Fu, Baoxiang Guan, Jianfeng Chen, Jorge M. Blando, James P. Allison, Liangwen Xiong, Sumit K. Subudhi, Jianjun Gao and Padmanee Sharma ()
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Lewis Zhichang Shi: MD Anderson Cancer Center
Tihui Fu: MD Anderson Cancer Center
Baoxiang Guan: MD Anderson Cancer Center
Jianfeng Chen: MD Anderson Cancer Center
Jorge M. Blando: The Immunotherapy Platform, MD Anderson Cancer Center
James P. Allison: The Immunotherapy Platform, MD Anderson Cancer Center
Liangwen Xiong: MD Anderson Cancer Center
Sumit K. Subudhi: MD Anderson Cancer Center
Jianjun Gao: MD Anderson Cancer Center
Padmanee Sharma: MD Anderson Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways.

Date: 2016
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DOI: 10.1038/ncomms12335

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