LAUSR

Recent advances in the understanding of tumor immunology have led to the development of various immunotherapeutic strategies, some of which show unprecedented clinical efficacies. Two of the most effective treatments, ipilimumab and pembrolizumab / nivolumab target the immune checkpoints factors CTLA-4 and PD-1, respectively. While not all patients respond to immunotherapy, those that do frequently show long-lasting clinical responses. These accomplishments have led to a surge in research focusing on the question how the immune system can be stimulated for more common durable therapy responses. A current focus of tumor immunological research is the identification of mechanisms allowing cancer cells to evade recognition and/or killing by the immune system while facing immunotherapy. For example, abrogation of interferon-γ signaling pathway has been shown to result in escape of immune surveillance after pembrolizumab treatment. However, it is likely that other tumor cell-intrinsic mechanisms play a role, too. To uncover novel pathways that are involved in resistance to immune checkpoint inhibitors, we aim to identify transcriptional changes in tumor cells that result from effector T-cell exposure. To this end, we established a co-culture platform of a panel of Mart1-expressing melanoma cell lines with primary CD8+ T cells expressing a matching TCR. The cell lines display varying degrees of sensitivity to T cells, allowing us to bioinformatically uncover differential expression depending on this range of sensitivities. Rather than concentrating on single genes, we have focused on pathways, gene sets and ontologies. These analyses have been integrated with various publically available transcriptomic data sets to identify a set of mechanisms that may contribute to T-cell mediated killing. We will systematically abrogate key factors using CRISPR technology in our co-culture platform and assess whether this affects T-cell mediated killing. Our ultimate goal is to test whether these factors, or their signaling pathways, are involved in resistance to immunotherapy in patients, and to develop new strategies to prevent immunotherapy resistance. Note: This abstract was not presented at the meeting. Citation Format: Thomas Kuilman, David Vredevoogd, Daniel S. Peeper. Uncovering novel signaling pathways that mediate tumor cell killing by T effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5627. doi:10.1158/1538-7445.AM2017-5627