Poster Presentation 36th Lorne Cancer Conference 2024

Targeting replication stress using a CHK1 inhibitor combination promotes anti-tumour immune responses which can be enhanced by reducing suppression from tumour-associated myeloid cells (#251)

Zhen Zeng 1 , Martina Proctor 1 , Rituparna Bhatt 1 , Katharine Irvine 1 , Sherry Wu 2 , Riccardo Dolcetti 3 4 5 6 , James Wells 6 , Jazmina-Libertad Gonzalez-Cruz 6 , Brian Gabrielli 1
  1. Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
  2. School of Biomedical Science, The University of Queensland, Brisbane, QLD, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  5. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
  6. Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

Introduction

Replication stress is a common feature of solid cancers. Drugs targeting replication stress, such as Checkpoint kinase 1 inhibitor (CHK1i), have demonstrated significant preclinical activity, especially in combination with replication stress-promoting chemotherapies. However, this has not translated into an effective clinical treatment, primarily due to high normal tissue toxicity. We have previously demonstrated that the combination of CHK1i SRA737 with a subclinical dose of hydroxyurea selectively targets a range of tumour types, with little normal tissue toxicity to even chemo-sensitive tissues. This CHK1i combination promotes a pro-inflammatory response and immunogenic cell death. It induces tumour regression, which is dependent on the adaptive immune response. Here we report the immune response triggered by CHK1i combination in mouse models and demonstrate that this response is suppressed by tumour-associated myeloid cells. 

Materials and Methods

Syngeneic mouse melanoma and ovarian cancer models were treated with the CHK1i combination. Tumour immune microenvironment (TIME) and peripheral immune cell responses were assessed by expression analysis and immune cell marker multiparameter flow cytometry.

Results and Discussion

CHK1i combination therapy consistently controlled tumour growth in a panel of syngeneic cancer models, but elicited different types of TIME in different models and cancers investigated. The combination enhanced anti-tumour immune responses independent of the initial TIME, including in tumours that were immunologically “cold”. The common features of the immune response in all tested models were increased cytolytic activity and reduced immune suppression in TIME. The CHK1i combination-induced tumour control was dependent on CD8+ T cells with a contribution from NK cells. Myeloid cells in TIME were immunosuppressive and this could be reversed by their depletion with CSF1R antibody or reducing tumour CSF1 expression. 

Conclusion

The data demonstrate that the CHK1i combination is highly selective with minimal normal tissue toxicity and can trigger an effective anti-tumour immune response in various tumours. Reducing tumour-associated myeloid number/activity enhanced anti-tumour immune responses triggered by the CHK1i combination. This work suggests that the myeloid component of tumours may significantly alter treatment responses by suppressing anti-tumour immune activity. Immunotherapies targeting tumour-associated myeloid cells represent a promising new field to amplify anti-tumour immunity induced by other treatments.