Abstract 20P
Background
Immune checkpoint inhibition (ICI) is an established treatment in PDL1-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined and BCBM still represents an area of unmet clinical need.
Methods
The tumour infiltrating lymphocytes (TILs) and the mRNA levels of 770 immune-related genes (NanoString nCounter Immuno-oncology IO360 panel) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcript and protein expression (immunohistochemistry) and its association with outcome (Kaplan-Meier Log-rank survival analysis) and T-cell depletion (Wilcoxon signed-rank t-test) was determined.
Results
A significant reduction of TILs was identified in the BCBMs in comparison to primary BCs. 11.5% of primary BCs had a high immune-infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate), whereas only 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. Compared to the primary BCs, we identified 112 downregulated genes in BCBM [false-discovery rate (FDR)<0.01, log2 fold-change (FC)>1.5], involved in matrix remodelling-metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion-migration. Four genes, ARG2, SOX2, EGF, NCAM1, were upregulated in BCBM (FDR<0.01), compared to the primary BCs. High mRNA expression of ARG2 in primary BCs was associated with a worse distant metastasis-free survival (DMFS, p=0.038), while ARG2 protein expression was associated with a worse breast-brain metastasis-free (BMFS, p=0.027) and overall survival (p=0.019). There was a significant difference between the transcript levels of ARG2 and cytotoxic cells, T-cells and CD8 T-cells in primary BCs (p<0.0001 for all comparisons), with higher transcript levels of T-cells and lower ARG2. In BCBM, the significant transcript difference remained between ARG2, Cytotoxic cells and T-cells but not CD8 T-cells (p=0.0014, p=0.021 and p=0.3219 respectively) with higher ARG2 and lower T-cell transcripts.
Conclusions
This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and as a prognostic biomarker in metastatic BC.
Legal entity responsible for the study
Breast Cancer group, University of Liverpool.
Funding
Infrastructure support from the Liverpool Experimental Cancer Medicine Centre (Grant Reference: C18616/A25153), the Clattterbridge Cancer Charity and the Liverpool University Hospitals NHS Foundation Trust. The study has also emanated from research supported in part by a Grant from Science Foundation Ireland under Grant number [20/FFP-P/8597 (DV)], Breast Cancer NOW Fellowship [Aug 2019 SF1310 (DV)] and Science Foundation Ireland Future for Frontiers Award, [19/FFP/6443 (LY)].
Disclosure
All authors have declared no conflicts of interest.