Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Beavis, Paul × End date: 2021 × Start date: 2021 × Type: Journal Article ×

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    MAIT cells regulate NK cell-mediated tumor immunity
    Petley, E ; Koay, H-F ; Henderson, MA ; Sek, K ; Todd, KL ; Keam, SP ; Lai, J ; House, IG ; Li, J ; Zethoven, M ; Chen, AXY ; Oliver, AJ ; Michie, J ; Freeman, AJ ; Giuffrida, L ; Chan, JD ; Pizzolla, A ; Mak, JYW ; McCulloch, TR ; Souza-Fonseca-Guimaraes, F ; Kearney, CJ ; Millen, R ; Ramsay, RG ; Huntington, ND ; McCluskey, J ; Oliaro, J ; Fairlie, DP ; Neeson, PJ ; Godfrey, D ; Beavis, PA ; Darcy, PK (NATURE PORTFOLIO, 2021-08-06)
    The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
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    Myeloma natural killer cells are exhausted and have impaired regulation of activation
    D'Souza, C ; Keam, SP ; Yeang, HXA ; Neeson, M ; Richardson, K ; Hsu, AK ; Canfield, R ; Bezman, N ; Robbins, M ; Quach, H ; Ritchie, DS ; Harrison, SJ ; Trapani, JA ; Prince, HM ; Beavis, PA ; Darcy, PK ; Neeson, PJ (FERRATA STORTI FOUNDATION, 2021-09)
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    CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy
    Giuffrida, L ; Sek, K ; Henderson, MA ; Lai, J ; Chen, AXY ; Meyran, D ; Todd, KL ; Petley, E ; Mardiana, S ; Molck, C ; Stewart, GD ; Solomon, BJ ; Parish, IA ; Neeson, PJ ; Harrison, SJ ; Kats, LM ; House, IG ; Darcy, PK ; Beavis, PA (NATURE PORTFOLIO, 2021-05-28)
    Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.