TY - JOUR
T1 - Enhanced immunogenicity of mitochondrial-localized proteins in cancer cells A C
AU - Prota, Gennaro
AU - Gileadi, Uzi
AU - Rei, Margarida
AU - Lechuga-Vieco, Ana Victoria
AU - Chen, Ji Li
AU - Galiani, Silvia
AU - Bedard, Melissa
AU - Lau, Vivian Wing Chong
AU - Fanchi, Lorenzo F.
AU - Artibani, Mara
AU - Hu, Zhiyuan
AU - Gordon, Siamon
AU - Rehwinkel, Jan
AU - Enríquez, Jose A.
AU - Ahmed, Ahmed A.
AU - Schumacher, Ton N.
AU - Cerundolo, Vincenzo
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/3
Y1 - 2020/3
N2 - Epitopes derived from mutated cancer proteins elicit strong antitumor T-cell responses that correlate with clinical efficacy in a proportion of patients. However, it remains unclear whether the subcellular localization of mutated proteins influences the efficiency of T-cell priming. To address this question, we compared the immunogenicity of NY-ESO-1 and OVA localized either in the cytosol or in mitochondria. We showed that tumors expressing mitochondrial-localized NY-ESO-1 and OVA proteins elicit significantdly higher frequencies of antigen-specific CD8+ T cells in vivo. We also demonstrated that this stronger immune response is dependent on the mitochondrial location of the antigenic proteins, which contributes to their higher steadystate amount, compared with cytosolic localized proteins. Consistent with these findings, we showed that injection of mitochondria purified from B16 melanoma cells can protect mice from a challenge with B16 cells, but not with irrelevant tumors. Finally, we extended these findings to cancer patients by demonstrating the presence of T-cell responses specific for mutated mitochondrial-localized proteins. These findings highlight the utility of prioritizing epitopes derived from mitochondrial- localized mutated proteins as targets for cancer vaccination strategies.
AB - Epitopes derived from mutated cancer proteins elicit strong antitumor T-cell responses that correlate with clinical efficacy in a proportion of patients. However, it remains unclear whether the subcellular localization of mutated proteins influences the efficiency of T-cell priming. To address this question, we compared the immunogenicity of NY-ESO-1 and OVA localized either in the cytosol or in mitochondria. We showed that tumors expressing mitochondrial-localized NY-ESO-1 and OVA proteins elicit significantdly higher frequencies of antigen-specific CD8+ T cells in vivo. We also demonstrated that this stronger immune response is dependent on the mitochondrial location of the antigenic proteins, which contributes to their higher steadystate amount, compared with cytosolic localized proteins. Consistent with these findings, we showed that injection of mitochondria purified from B16 melanoma cells can protect mice from a challenge with B16 cells, but not with irrelevant tumors. Finally, we extended these findings to cancer patients by demonstrating the presence of T-cell responses specific for mutated mitochondrial-localized proteins. These findings highlight the utility of prioritizing epitopes derived from mitochondrial- localized mutated proteins as targets for cancer vaccination strategies.
UR - http://www.scopus.com/inward/record.url?scp=85084960980&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-19-0467
DO - 10.1158/2326-6066.CIR-19-0467
M3 - 文章
C2 - 32205315
AN - SCOPUS:85084960980
SN - 2326-6066
VL - 8
SP - 685
EP - 697
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 5
ER -