Poster Presentation NSW State Cancer Conference 2023

Activating the endogenous armoury: anticancer drugs as immunotherapy enablers (#160)

Hieu Nguyen 1 , Dannielle H Upton 1 2 , Aaminah Khan 1 2 , Holly Holliday 1 2 , Oluwaseyi S Ogunmodede 3 , Kerry-Anne Rye 3 , Maria Tsoli 1 2 , Benjamin S Rayner 1 2 , David S Ziegler 1 2 4
  1. Children's Cancer Institute, Sydney, NSW, Australia
  2. School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
  3. School of Biomedical Science, University of New South Wales, Sydney, NSW, Australia
  4. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia

As with many cancers, the tumour microenvironment surrounding diffuse intrinsic pontine glioma (DIPG) – a deadly, incurable paediatric brain cancer – contains a significant proportion of macrophage infiltrate and resident microglia1. Despite their abundance, DIPG is considered immune “cold” due to the polarisation of these immune cells towards an anti-inflammatory phenotype1, 2. Our research is focused on targeting the epigenetic machinery that drives DIPG tumorgenicity. As single agents, we demonstrated that inhibiting the histone chaperone complex Facilitates Chromatin Transcription Interestingly, there is evidence that these compounds also have the ability to invoke an interferon response3, dampening immunosuppression4 and activating inflammatory pathways5. Consequently, they offer the dual potential within the setting of DIPG of both targeting tumour cells and enhancing the inflammatory cell-mediated defence mechanisms required to suppress DIPG tumorgenicity.

Here we provide in vitro evidence that both macrophages differentiated from THP-1 (an established human monocyte cell line), and primary human monocyte-derived macrophages (HMDM) exposed to clinically relevant doses of CBL0137, JQ1 or TAK-981 exhibit polarisation towards a pro-inflammatory M1 phenotype. This response includes upregulation of the M1 markers CD86, Interferon regulatory factors (IRF1, 5 and 8), resulting in the initiation of an inflammatory response through sustained upregulation of interferon beta, interleukin 6, monocyte chemoattractant protein-1 and tumour necrosis factor alpha expression, whilst concomitantly decreasing anti-inflammatory M2 phenotypical markers such as early growth response 2 and fibronectin. Combined, these data suggest that these clinically relevant anti-cancer agents potentially offer a “double-punch strategy” against DIPG. We aim to confirm our exciting in vitro findings in immunocompetent mouse models of DIPG, further informing clinical translation of these compounds, and ultimately providing better therapeutic options for DIPG patients.

 

 

 

 

  1. Ross, J.L. et al. Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma. Brain 144, 53-69 (2021).
  2. Arcuri, C. et al. Microglia-glioma cross-talk: a two way approach to new strategies against glioma. Front Biosci (Landmark Ed) 22, 268-309 (2017).
  3. Leonova, K. et al. TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells. Elife 7 (2018).
  4. Joshi, S. et al. SF2523: Dual PI3K/BRD4 Inhibitor Blocks Tumor Immunosuppression and Promotes Adaptive Immune Responses in Cancer. Mol Cancer Ther 18, 1036-1044 (2019).
  5. Nakamura, A. et al. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood 139, 2770-2781 (2022).