Emerging role of immune checkpoint inhibitors and their relevance for the cardiovascular system
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Lars Michel1 · Matthias Totzeck1 · Lorenz Lehmann2,3 · Daniel Finke2,3 1
Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Essen, Germany 2 Cardio-oncology Unit, Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany 3
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany
Emerging role of immune checkpoint inhibitors and their relevance for the cardiovascular system The role of immune checkpoints Inflammation is orchestrated by a complex crosstalk between immune cells and peripheral organs. By stimulation or inhibition of particular signaling pathways, immune reactions can be triggered or inhibited. This balance prevents an ineffective immune response as well as an excessive reaction. Immune checkpoints play a pivotal role in this process by inhibiting the activity of the adaptive immune system. The main immune checkpoints are programmed cell death protein 1 (PD1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) [1]. By inhibiting T cell activation in response to recognition of specific antigens, which serves to initiate a targeted immune response, immune checkpoints dampen immune activity and counterbalance overwhelming inflammation that could damage uninvolved tissue and organs and prevent autoimmunity. CTLA4 binds specific ligands expressed on peripheral cells and thereby inhibits CD28-mediated co-stimulation of T cell activation and limits T cell susceptibility to antigen presentation [2]. PD1 induces specific downstream signaling pathways upon ligation with its ligands PDL1 and PDL1, which serve to inhibit T cell activity [1].
Immune checkpoint inhibitor therapy Immune checkpoint inhibitors (ICI) are monoclonal antibodies that specifically target PD1/PDL1 or CTLA4. By inhibiting the immune checkpoint pathways, ICIs stimulate the adaptive immune response. Evasion of immune response is a hallmark of cancer [3, 4]. To achieve this, cancercells showreduced expression of self-antigens and can show a strong expression of immune checkpoint ligands such as PDL1 to further inhibit a tumorspecific immune reaction by activation of immune checkpoint signaling. Blockade of these escape mechanisms by ICI aims to trigger an anti-tumor immune response [4]. The first ICI was the CTLA4 antibody ipilimumab, approval of which was granted in 2011 for melanoma [4]. Nivolumabwas the firstICI targeting PD1 and was approved in 2014 for melanoma [5, 6]. Combined CTLA4- and PD1blocking therapy is a non-redundant approach as CTLA4 interferes in the early phase of T cell activation, which is mainly located in the crosstalk between T cells and antigen presenting cells (APC). On the other hand, PD1 may interfere with later inhibition of T cell activity within the immediate tumor environment [7]. This was confirmed in initial studies of ipilimumab and nivolumab combination
therapy for melanoma therapy [8]. ICI have improved the treatment of differ
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