Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Darcy, Phillip × Author: Dushyanthen, Sathana × Author: Loi, Sherene × End date: 2019 × Type: Journal Article ×

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    Relevance of tumor-infiltrating lymphocytes in breast cancer
    Dushyanthen, S ; Beavis, PA ; Savas, P ; Teo, ZL ; Zhou, C ; Mansour, M ; Darcy, PK ; Loi, S (BMC, 2015-08-24)
    While breast cancer has not been considered a cancer amenable to immunotherapeutic approaches, recent studies have demonstrated evidence of significant immune cell infiltration via tumor-infiltrating lymphocytes in a subset of patient tumors. In this review we present the current evidence highlighting the clinical relevance and utility of tumor-infiltrating lymphocytes in breast cancer. Retrospective and prospective studies have shown that the presence of tumor-infiltrating lymphocytes is a prognostic marker for higher responses to neoadjuvant chemotherapy and better survival, particularly in triple negative and HER2-positive early breast cancer. Further work is required to determine the immune subsets important in this response and to discover ways of encouraging immune infiltrate in tumor-infiltrating lymphocytes-negative patients.
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    Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer
    Dushyanthen, S ; Teo, ZL ; Caramia, F ; Savas, P ; Mintoff, CP ; Virassamy, B ; Henderson, MA ; Luen, SJ ; Mansour, M ; Kershaw, MH ; Trapani, JA ; Neeson, PJ ; Salgado, R ; McArthur, GA ; Balko, JM ; Beavis, PA ; Darcy, PK ; Loi, S (NATURE PUBLISHING GROUP, 2017-09-19)
    The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.