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J Immunol. 2017 Aug 1;199(3):974-981. doi: 10.4049/jimmunol.1700088. Epub 2017 Jun 23.

Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity.

Author information

1
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom.
2
Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
3
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
4
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; and.
5
Department of Immunology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030.
6
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; p.j.l.lane@bham.ac.uk.

Abstract

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

PMID:
28646041
PMCID:
PMC5523579
DOI:
10.4049/jimmunol.1700088
[Indexed for MEDLINE]
Free PMC Article

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