Targeting and retention of HPV16 E7 to the endoplasmic reticulum enhances immune tumour protection.
The endoplasmic reticulum (ER) is where the major histocompatibility complex (MHC) class I molecules are loaded with epitopes to cause an immune cellular response. Most of the protein antigens are degraded in the cytoplasm to amino acids and few epitopes reach the ER. Antigen targeting of this organelle by Calreticulin (CRT) fusion avoids this degradation and enhances the immune response. We constructed a recombinant adenovirus to express the E7 antigen with an ER-targeting signal peptide (SP) plus an ER retention signal (KDEL sequence). In cell-culture experiments we demonstrated that this new E7 antigen, SP-E7-KDEL, targeted the ER. Infection of mice with this recombinant adenovirus that expresses SP-E7-KDEL showed interferon induction and tumour-protection response, similar to that provided by an adenovirus expressing the E7 antigen fused to CRT. This work demonstrated that just by adding a SP and the KDEL sequence, antigens can be targeted and retained in the ER with a consequent enhancement of immune response and tumour protection. These results will have significant clinical applications.
Loera-Arias
M J
MJ
Departamento de Histología, Facultad de Medicina. Universidad Autónoma de Nuevo León, Monterrey, N.L., México.
Martínez-Pérez
A G
AG
Barrera-Hernández
A
A
Ibarra-Obregón
E R
ER
González-Saldívar
G
G
Martínez-Ortega
J I
JI
Rosas-Taraco
A
A
Villanueva-Olivo
A
A
Esparza-González
S C
SC
Villatoro-Hernandez
J
J
Saucedo-Cárdenas
O
O
Montes-de-Oca-Luna
R
R
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D037282:Calreticulin / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000517:prevention & control*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D037282:Calreticulin; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma