Andrea Mahr

Annexin A1 on the Surface of Early Apoptotic Cells Suppresses CD8 + T Cell Immunity

Prevention of an immune response against self-antigens derived from apoptotic cells is essential to preclude autoimmune and chronic inflammatory diseases. Here, we describe apoptosis induced externalization of endogenous cytosolic annexin 1 initiating an anti-inflammatory effector mechanism that suppresses the immune response against antigens of apoptotic cells. Cytosolic annexin 1 rapidly translocated to the apoptotic cell surface and inhibited dendritic cell (DC) activation induced by Toll like receptors (TLR). Annexin 1-inhibited DC showed strongly reduced secretion of pro-inflammatory cytokines (e.g. TNF and IL-12) and costimulatory surface molecules (e.g. CD40 and CD86), while anti-inflammatory mediators like PD-L1 remained unchanged. T cells stimulated by such DC lacked secretion of interferon-γ (IFN-γ) and TNF but retained IL-10 secretion. In mice, annexin 1 prevented the development of inflammatory DC and suppressed the cellular immune response against the model antigen ovalbumin (OVA) expressed in apoptotic cells. Furthermore, annexin 1 on apoptotic cells compromised OVA-specific tumor vaccination and impaired rejection of an OVA-expressing tumor. Thus, our results provide a molecular mechanism for the suppressive activity of apoptotic cells on the immune response towards apoptotic cell-derived self-antigens. This process may play an important role in prevention of autoimmune diseases and of the immune response against cancer.

The tolerogenic function of annexins on apoptotic cells is mediated by the annexin core domain

Immunological tolerance is constantly being maintained in the periphery by dendritic cells processing material from apoptotic cells (ACs) in the steady-state. Although research has focused on the uptake of ACs by phagocytes, tolerogenic signals exposed by the ACs are much less well defined. In this article, we show that the annexin (Anx) family members AnxA5 and AnxA13 translocate to the surface of ACs to function as redundant tolerogenic signals in vitro and in vivo. Exposure of bone marrow–derived dendritic cells to AnxA5 or AnxA13 in vitro resulted in the inhibition of both proinflammatory cytokine secretion and the upregulation of costimulatory molecules upon TLR stimulation. The highly conserved Anx core domain was sufficient to mediate these effects, whereas recognition by N-formyl peptide receptor family members was dispensable. In vivo, coinjection of OVA-expressing and Anx-expressing ACs prevented induction of Ag-specific CD8+ T cells. Moreover, mice immunized with Anx-expressing ACs became refractory to an antigenic challenge. These results suggest that several Anxs contribute to AC-induced suppression of dendritic cell activation. Therefore, manipulating Anx-mediated immunosuppression may prove beneficial for patients with cancer or autoimmune diseases and chronic inflammatory disorders.

The right patient for the right therapy: 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 11-13, 2015.

HNPCC Hereditary nonpolyposis colorectal cancer HPV Human papilloma virus HSCT Hematopoietic stem cell transplantation IDH1 Isocitrate dehydrogenase 1 IFN Interferon IHC Immuno-histochemistry IL Interleukin iNOS Inducible nitric oxide synthetase mAb Monoclonal antibody MDACC MD Anderson Cancer Center MDSC Myeloid-derived suppressor cells MEK MAP kinase kinase MHC Major histocompatibility complex MMP-2 Matrix metalloproteinase-2 MMR Mismatch repair MSI Microsatellite instability mTEC Medullary thymic epithelial cells NGS Next-generation sequencing NHL Non-Hodgkin lymphoma OS Overall survival OVA Ovalbumin PBMC Peripheral blood mononuclear cells PCR Polymerase chain reaction PD-1 Programmed death-1 PDAC Pancreatic ductal adenocarcinoma PFS Progression-free survival RIP Rat insulin promoter RNA Ribonucleic acid SLP Synthetic long peptide TAM Tumor-associated macrophages TCGA The Cancer Genome Atlas TCR T cell receptor Teff Effector T cell TGF Transforming growth factor TIL Tumor-infiltrating lymphocytes