Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy
Authors:Daniel Baumann1,2 and Rienk Offringa1,2
1 Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany.
2 Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany.
Keywords:
cancer immunotherapy, immune checkpoint blockade, combinatorial immunotherapy, immunogenic cell death, cytostatic agents, MEK inhibition, MAPK, CD40, agonist.
Corresponding Author(s):
Conflict of interest statement:
The authors declare that there is no conflict of interest.
Please cite this article as:
Daniel Baumann and Rienk Offringa (2020). Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy. Cell Stress 4(10): 248-251. doi: 10.15698/cst2020.10.233
© 2020 Baumann and Offringa. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
The widespread application of immune-checkpoint blockade (ICB) has resulted in unprecedented response rates in patients with immunogenic cancers, such as melanoma and lung cancer. However, sub-groups of patients with these indications do not respond to ICB, and the same applies to patients with other cancer types. Mechanisms of resistance to ICB include low tumor immunogenicity associated with low T cell infiltration (‘cold’ tumors), suppression of anti-tumor immunity by immunosuppressive cells in the tumor microenvironment (TME), lack of antigen-presentation and immune escape (e.g. by downregulation of MHC-I on tumor cells) as well as oncologic pathways that suppress immune responses. Combination strategies, involving cytostatic drugs, harbor the potential to overcome refractoriness to immunotherapy. However, suppression of immune cell function by cytostatic drugs may limit the efficacy. In our study, we show that combination treatment of targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) and agonist immunostimulatory anti-CD40 antibody (Ab) is particularly suitable in counteracting aforementioned ICB resistance mechanisms (Fig. 1).