Remodelling of the immune landscape and its effect of tumour immunity in a model of IFNy-insensitive murine melanoma

Thesis

Loss of IFNγ-sensitivity by tumour cells appears to enable evasion against T cell-dependent cytotoxicity, as some cancers lacking IFNγ-signalling demonstrate clinical resistance to checkpoint immunotherapy. However, recent studies have demonstrated that IFNγ-resistant tumours can sensitize the immune system for improved anti-tumour immunity. As a pleiotropic cytokine, the functions of IFNγ appears to have disparate modalities depending on context and magnitude of signalling in the tumour microenvironment.

In this thesis, we adopted a B16F10 murine melanoma model deficient in IFNGR1 and hypothesized that IFNGR1KO tumours would outgrow WT tumours due to impaired antigen presentation to CD8+ T cells. Unexpectedly, IFNGR1KO tumours implanted into independent mice grew at equivalent rates despite minimal MHC-I/II expression on KO tumours. However, when WT and KO cells were admixed prior to implantation, the expected clinical phenotype was restored, as KO cells outgrew WT and preferential recruitment of CD8+ T cells in ‘WT zones’ is observed. To explain this paradox, we measured the levels of intratumoural IFNγ via ELISA and found an accumulation within KO tumours compared to WT. We hypothesized that this level of IFNγ is capable of triggering active re-modelling of the tumour microenvironment which in turn preserves anti-tumour immunity. Analysis of single-cell RNAseq data from tumour-infiltrating CD45+ cells found that transcriptional changes within the myeloid compartment to promote less pro-tumourigenic macrophages may be key to modulating tumour control. Consequently, future experiments will attempt to elucidate whether macrophages are the key to enabling CD8+ T cell-dependent anti-tumour responses in KO tumours. This work highlights MHC-independent pathways within the immune microenvironment which are absent or enhanced following loss of IFNγ sensitivity, to better understand the paradoxical effects of IFNγ on tumour control over time.

Authors: Lau, VWC

• DOI: 10.5287/ora-zrxj4waom
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: immunology; cytokines; inflammation; cancer
• Subjects: immunology; cancer