Mechanisms of resistance to PD-1 based immunotherapy in melanoma liver metastases

Abstract

In the past decade, immunotherapy advancements have significantly benefited advanced melanoma patients, yet treatment failure remains common, affecting half of patients due to resistance to checkpoint inhibitors. Recent data suggests that different sites of metastasis (mets) respond differently to anti-PD-1-based immunotherapy, particularly the liver, and can impact overall response and survival. It remains unclear how liver mets may affect the systemic immune response. This thesis aims to explore microenvironment variations in liver mets and systemic effects, identifying potential resistance mechanisms.

This study compared the immune microenvironment between liver mets and other sites, revealing a distinct profile with reduced T cell infiltration, lower PD-1 but increased TIM-3 expression. Systemically we showed patients with liver mets had increased ‘classical’ monocytes in circulation and reduced T cell infiltration in non-liver sites. Tumour hypoxia analysis indicated reduced CAIX expression in the liver, coupled with heightened glycolytic activity. An association between regional GLUT1 expression and reduced T cell infiltration in both liver and non-liver sites suggested a potential hypoxia-mediated T cell exclusion mechanism.

Based on these finding, we hypothesised a potential benefit of adding a VEGF inhibitor to anti-cancer treatments for patients with liver mets. A pan-cancer meta-analysis supported this, revealing improved survival in patients treated with concurrent VEGF inhibitors compared to standard treatment alone. Additionally, the development of a patient-derived explant model for testing personalized treatment response and resistance mechanisms was initiated.

In summary, the thesis provides a comprehensive characterisation of liver mets and their impact on local and systemic tumour immunity in advanced melanoma patients. The identified mechanisms, particularly hypoxia, offer potential targets for future preclinical models and functional studies.