Rational therapeutic modulation of the tumor microenvironment sensitizes cancers to immune checkpoint blockade
Rachael M. Zemek1,2, Emma De Jong3, Wee Long Chin1,4,5, Vanessa Fear1,2, Cath Forbes1,2, Tom Casey1,2, Danika Hope1,2, Michael J. Millward4,5, Anna K. Nowak4,5, Timo Lassman3, Anthony Bosco3, Richard A. Lake1,2, Willem J. Lesterhuis1,2*
1School of Biomedical Sciences, University of Western Australia (UWA), Perth, Australia; 2National Centre for Asbestos Related Diseases; 3Telethon Kids Institute; 4School of Medicine, UWA; 5Department of Medical Oncology, Charles Gairdner Hospital
*Corresponding author: email@example.com
Antibodies targeting immune checkpoints prolong survival in a number of patients and cancer types. However, most patients do not respond, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments.
Here, we provide a detailed map of the pretreatment tumor microenvironment associated with response. We used bulk RNAseq, flow cytometry and single cell RNAseq data obtained from pretreatment responding and non-responding tumor samples in controlled experiments involving monoclonal cancer cell lines in inbred mice treated with antibodies against CTLA4 and PD-L1.
We found that the presence of natural killer cells in tumor infiltrates was necessary for responses to occur. In addition, prior to treatment, responsive tumors displayed an inflammatory gene expression signature, which was corroborated in a dataset of patients with diverse cancers treated with immune checkpoint blockade. We identified key positive and negative upstream regulators that were predicted to induce the response-associated signature. Pretreatment of difficult-to-treat mouse tumor models, using a combination of therapeutics targeting these upstream regulators resulted in full cures when they were subsequently treated with immune checkpoint blockade.
Our results identify a cellular and molecular signature associated with response to immune checkpoint blockade, which can be therapeutically attained and monitored before treatment to improve efficacy.