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Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression

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posted on 2023-01-24, 07:55 authored by A Giannoudis, Damir VareslijaDamir Vareslija, V Sharma, R Zakaria, A Platt-Higgins, PS Rudland, MD Jenkinson, Leonie YoungLeonie Young, C Palmieri

Background: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined.

Materials and methods: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined.

Results: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01).

Conclusion: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome.

Funding

Liverpool University Hospitals NHS Foundation Trust

Liverpool Experimental Cancer Medicine Centre [grant number C18616/A25153]

Clatterbridge Cancer Charity

Science Foundation Ireland [grant number 20/FFP-P/8597]

Breast Cancer NOW Fellowship [grant number Aug 2019 SF1310]

Science Foundation Ireland Future for Frontiers Award [grant number 19/FFP/6443]

History

Comments

The original article is available at https://www.esmoopen.com/

Published Citation

Giannoudis A. et al. Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression. ESMO Open. 2022;7(6):100636.

Publication Date

21 November 2022

PubMed ID

36423363

Department/Unit

  • School of Pharmacy and Biomolecular Sciences
  • Surgery

Research Area

  • Cancer

Publisher

Elsevier BV

Version

  • Published Version (Version of Record)