ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Systematic Analysis of Chemotherapy and Immune Checkpoint Blockade Combinations that Lead to Durable Responses (#134)

Nicola Principe 1 2 , Wayne J Aston 2 , Danika E Hope 2 , Caitlin M Tilsed 1 2 , Scott A Fisher 1 2 , Maud Jansen 3 , Louis Boon 4 , Ian M Dick 2 , Wee Loong Chin 2 5 6 , Anna K Nowak 2 5 , Alison M McDonnell 6 , Richard A Lake 1 2 , Jonathan Chee 1 2 , Willem Lesterhuis 1 2 6
  1. School of Biomedical Science, University of Western Australia, Crawley, WA, Australia
  2. National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
  3. Radbound Institute for Molecular Life Science, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, The Netherlands
  4. Polpharma Biologics, Utrecht, Netherlands
  5. School of Medicine, University of Western Australia, Nedlands, WA, Australia
  6. Telethon Kids Institute, Perth, WA, Australia

Immune checkpoint blockade (ICB) that enhances the anti-tumour immune response is a treatment option for multiple cancer types. However as a stand-alone therapy, objective response rates only occur in a minority of patients. Chemotherapy is widely used in combination with ICB. Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. Here, we investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with ICB (anti-CTLA-4/anti-PD-L1) in two murine mesothelioma cancer models from two different genetic backgrounds. We identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Vinorelbine displayed an antagonistic interaction with ICB, while 5-Fluorouracil (5-FU) or cisplatin were additive when combined with ICB. Using flow cytometry and bulk RNAseq, we characterised the tumour immune milieu to understand mechanisms of additive chemo-immunotherapy combinations. Both 5-FU and cisplatin in combination with ICB resulted in a profound expansion of tumour draining lymph nodes. Both chemo-immunotherapies markedly increased CD8+ and CD4+ T cell activation and depleted CD4+Foxp3+ regulatory T cells in tumours. 5-FU treated tumours were enriched for immune-related genes, and addition of ICB to 5-FU increased the expression of proinflammatory genes TNF