In:
The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 194.41-194.41
Abstract:
Many immunotherapies act by enhancing T cell killing of tumor cells. CD8+ cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Here we show that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor (TNF) or lymphotoxin beta receptor agonist (LTβRag) rescues expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo, and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.202.Supp.194.41
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2019
detail.hit.zdb_id:
1475085-5