Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy

被引:51
作者
Baumann, Daniel [1 ,2 ]
Haegele, Tanja [1 ]
Mochayedi, Julian [1 ]
Drebant, Jennifer [1 ]
Vent, Caroline [1 ,2 ]
Blobner, Sven [1 ]
Noll, Julia Han [1 ]
Nickel, Irena [1 ]
Schumacher, Corinna [1 ]
Boos, Sophie Luise [1 ,3 ]
Daniel, Aline Sophie [1 ]
Wendler, Susann [1 ,2 ]
Volkmar, Michael [1 ,2 ]
Strobel, Oliver [2 ]
Offringa, Rienk [1 ,2 ]
机构
[1] German Canc Res Ctr Heidelberg, Dept Mol Oncol Gastrointestinal Tumors, D-69120 Heidelberg, Baden Wuerttemb, Germany
[2] Heidelberg Univ Hosp, Dept Surg, D-69120 Heidelberg, Baden Wuerttemb, Germany
[3] Ludwig Maximilians Univ Munchen, Dept Oncogen Signaling Pathways Colorectal Pancre, D-80539 Munich, Bavaria, Germany
关键词
T-CELL IMMUNITY; DENDRITIC CELLS; CANCER; COMBINATION; CARCINOMA; BLOCKADE; LINES; CD40; INDUCTION; PD-1;
D O I
10.1038/s41467-020-15979-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment.
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页数:18
相关论文
共 70 条
  • [1] Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma
    Aguirre, Andrew J.
    Hruban, Ralph H.
    Raphael, Benjamin J.
    [J]. CANCER CELL, 2017, 32 (02) : 185 - +
  • [2] Targeted Therapies for Pancreatic Cancer
    Amanam, Idoroenyi
    Chung, Vincent
    [J]. CANCERS, 2018, 10 (02)
  • [3] The transition from HLA-I positive to HLA-I negative primary tumors: the road to escape from T-cell responses
    Aptsiauri, Natalia
    Ruiz-Cabello, Francisco
    Garrido, Federico
    [J]. CURRENT OPINION IN IMMUNOLOGY, 2018, 51 : 123 - 132
  • [4] Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function
    Boni, Andrea
    Cogdill, Alexandria P.
    Dang, Ping
    Udayakumar, Durga
    Njauw, Ching-Ni Jenny
    Sloss, Callum M.
    Ferrone, Cristina R.
    Flaherty, Keith T.
    Lawrence, Donald P.
    Fisher, David E.
    Tsao, Hensin
    Wargo, Jennifer A.
    [J]. CANCER RESEARCH, 2010, 70 (13) : 5213 - 5219
  • [5] CD4+ T cell help in cancer immunology and immunotherapy
    Borst, Jannie
    Ahrends, Tomasz
    Babala, Nikolina
    Melief, Cornelis J. M.
    Kastenmueller, Wolfgang
    [J]. NATURE REVIEWS IMMUNOLOGY, 2018, 18 (10) : 635 - 647
  • [6] BRANDES LJ, 1983, CANCER RES, V43, P2831
  • [7] BRINKLEY BR, 1980, CANCER RES, V40, P3118
  • [8] CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer
    Byrne, Katelyn T.
    Vonderheide, Robert H.
    [J]. CELL REPORTS, 2016, 15 (12): : 2719 - 2732
  • [9] CAILLEAU R, 1978, IN VITRO CELL DEV B, V14, P911
  • [10] AmiGO: online access to ontology and annotation data
    Carbon, Seth
    Ireland, Amelia
    Mungall, Christopher J.
    Shu, ShengQiang
    Marshall, Brad
    Lewis, Suzanna
    [J]. BIOINFORMATICS, 2009, 25 (02) : 288 - 289