Home » Key Drug Discovery Articles » The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8T cells

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8T cells

Significance Statement

Tumor development is associated with various immunosuppressive mechanisms that affect T cell responses, including those potentially elicited by anti-tumor vaccination or adoptive immunotherapy. To increase the efficiency of such therapies one can try either to decrease the immunosuppressive environment created by the tumor or to render T cells less susceptible to immunosuppression. We observed high expression of A20 (tnfaip3) transcripts, a molecule controlling NF-κB activation, in dysfunctional CD8 T cells in an autochthonous mouse melanoma. Over-expression of A20 by retroviral transduction of CD8 T cells dampened their intra-tumor accumulation and anti-tumor activity. We further showed that T cells with selective deletion of A20 in mature T lymphocytes had a higher sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNg, correlated with sustained nuclear expression of NF-κB components c-Rel/RelA. Furthermore adoptively transferred anti-tumor CD8 T cells deleted of A20 possessed heightened anti-tumor activity in vivo correlated with their high capacity to produce IFNγ and TNFα while expressing reduced levels of PD-1. This work thus contributed to the identification of a major pathway affected in dysfunctional T cells within tumors, which can apparently be reversed, without pathologic consequences.

A20 - Global Medical Discovery

 

 

 

 

 

 

Journal Reference

Giordano M1, Roncagalli R1, Bourdely P1, Chasson L1, Buferne M1, Yamasaki S2, Beyaert R3, van Loo G3, Auphan-Anezin N1, Schmitt-Verhulst AM1, Verdeil G4.

Proc Natl Acad Sci U S A. 2014 ;111(30):11115-20.

1Centre d’Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;and

2Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;and

3Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium; andInflammation Research Center, Vlaams Instituut voor Biotechnologie, B-9052 Ghent, Belgium.and

4Centre d’Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France; [email protected]

 

Abstract

 The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth.Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

Go To PubMed