Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Enhancing current immunotherapies by improving T cell infiltration into solid tumours (#53)

Emily B Derrick 1 2 , Imran G House 1 2 , Junyun Lai 1 2 , Phil K Darcy 1 2 , Paul A Beavis 1 2
  1. Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  2. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia

Immune checkpoint blockade (ICB) has revolutionised the treatment of numerous cancer types, particularly those with a high mutational burden such as melanoma and non-small cell lung carcinoma. ICB targets immune-inhibitory molecules on the surface of T cells, unleashing their anti-tumour potential. Despite ICB’s success, a high frequency of patients fail to respond to ICB. A key limiting factor to ICB responses is the number of T cells that are able to infiltrate the tumour microenvironment. T cell infiltration in the context of ICB has been shown to be dependent on attractant molecules CXCL9 and CXCL10. CXCL9 and CXCL10 are chemokines expressed by macrophages within the tumour microenvironment that attract T cells to the tumoral site. A pan-cancer meta-analysis has identified CXCL9 expression as one of the strongest predictors for a positive response to ICB. In addition, the expression of CXCL9 and CXCL10 is predictive of improved T cell infiltration and patient survival in melanoma and urothelial carcinoma cohorts that have received ICB. We have identified regulators of chemokine production using a novel reporter macrophage cell line that was generated using CRISPR/Cas9 homology directed repair. These identified regulators can be targeted therapeutically to improve chemokine expression and subsequent T cell infiltration into tumours, priming tumours to respond positively to ICB. By targeting chemokine regulators in combination with ICB, we hope to improve the efficacy of ICB and clinical outcomes for patients.