ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T cell therapy in mice

Item Type:	Article
Title:	ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T cell therapy in mice
Creators Name:	Schmidt, K. and Keller, C. and Kühl, A.A. and Textor, A. and Seifert, U. and Blankenstein, T. and Willimsky, G. and Kloetzel, P.M.
Abstract:	Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by major histocompatibility complex class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on non-cancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER). We show here that ERAP1 is critically involved in the process of tumor rejection and assumes a dual role by independently operating on both sides. Direct presentation of two MHC-I restricted epitopes of a cancer-driving transplantation rejection antigen through ERAP1 moderately affected tumor rejection by adoptively transferred T-cell receptor (TCR) gene-modified T cells in each case. ERAP1 expression by antigen cross-presenting cells of the ATT recipients was critical for expansion of therapeutic monospecific T cells and correlated with tumor rejection. Specifically, lack of ERAP1 expression in the ATT recipient's non-cancerous cells enabled progression of pMHC-I-positive, IFNγ-responsive tumors, despite the presence of antigen-specific functional cytotoxic T lymphocytes. These data reveal a decisive role for ERAP1 in T cell mediated tumor rejection and will enhance the choice of MHC-I-restricted epitopes targeted by adoptive T cell transfer. Significance: This study demonstrates a role of ERAP1 in the efficacy of adoptive T-cell transfer and has potential to improve personalized T-cell therapy for solid tumors.
Keywords:	Adoptive Immunotherapy, Aminopeptidases, Animal Disease Models, Antigen Presentation, Cross-Priming, Cytotoxic T-Lymphocytes, Endoplasmic Reticulum, Epitopes, Graft Rejection, Hepatocellular Carcinoma, Histocompatibility Antigens Class I, Inbred C57BL Mice, Knockout Mice, Liver Neoplasms, Minor Histocompatibility Antigens, T-Cell Antigen Receptors, Treatment Outcome, Tumor Cell Line, Tumor-Infiltrating Lymphocytes, Animals, Mice
Source:	Cancer Research
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	78
Number:	12
Page Range:	3243-3254
Date:	June 2018
Official Publication:	https://doi.org/10.1158/0008-5472.CAN-17-1946
PubMed:	View item in PubMed

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