TY - JOUR

T1 - T cell recognition of novel shared breast cancer antigens is frequently observed in peripheral blood of breast cancer patients

AU - Viborg, Nadia

AU - Ramskov, Sofie

AU - Andersen, Rikke Sick

AU - Sturm, Theo

AU - Fugmann, Tim

AU - Bentzen, Amalie Kai

AU - Rafa, Vibeke Mindahl

AU - Straten, Per thor

AU - Svane, Inge Marie

AU - Met, Özcan

AU - Hadrup, Sine Reker

PY - 2019

Y1 - 2019

N2 - Advances within cancer immunotherapy have fueled a paradigm shift in cancer treatment, resulting in increasing numbers of cancer types benefitting from novel treatment options. Despite originally being considered an immunologically silent malignancy, recent studies encourage the research of breast cancer immunogenicity to evaluate immunotherapy as a treatment strategy. However, the epitope landscape in breast cancer is minimally described, limiting the options for antigen-specific, targeted strategies. Aromatase, never in mitosis A-related kinase 3 (NEK3), protein inhibitor of activated STAT3 (PIAS3), and prolactin are known as upregulated proteins in breast cancer. In the present study, these four proteins are identified as novel T cell targets in breast cancer. From the four proteins, 147 peptides were determined to bind HLA-A*0201 and -B*0702 using a combined in silico/in vitro affinity screening. T cell recognition of all 147 peptide-HLA-A*0201/-B*0702 combinations was assessed through the use of a novel high-throughput method utilizing DNA barcode labeled multimers. T cell recognition of sequences within all four proteins was demonstrated in peripheral blood of patients, and significantly more T cell responses were detected in patients compared to healthy donors for both HLA-A*0201 and -B*0702. Notably, several of the identified responses were directed toward peptides, with a predicted low or intermediate binding affinity. This demonstrates the importance of including low-affinity binders in the search for epitopes within shared tumor associated antigens (TAAs), as these might be less subject to immune tolerance mechanisms. The study presents four novel TAAs containing multiple possible targets for immunotherapy of breast cancer.

AB - Advances within cancer immunotherapy have fueled a paradigm shift in cancer treatment, resulting in increasing numbers of cancer types benefitting from novel treatment options. Despite originally being considered an immunologically silent malignancy, recent studies encourage the research of breast cancer immunogenicity to evaluate immunotherapy as a treatment strategy. However, the epitope landscape in breast cancer is minimally described, limiting the options for antigen-specific, targeted strategies. Aromatase, never in mitosis A-related kinase 3 (NEK3), protein inhibitor of activated STAT3 (PIAS3), and prolactin are known as upregulated proteins in breast cancer. In the present study, these four proteins are identified as novel T cell targets in breast cancer. From the four proteins, 147 peptides were determined to bind HLA-A*0201 and -B*0702 using a combined in silico/in vitro affinity screening. T cell recognition of all 147 peptide-HLA-A*0201/-B*0702 combinations was assessed through the use of a novel high-throughput method utilizing DNA barcode labeled multimers. T cell recognition of sequences within all four proteins was demonstrated in peripheral blood of patients, and significantly more T cell responses were detected in patients compared to healthy donors for both HLA-A*0201 and -B*0702. Notably, several of the identified responses were directed toward peptides, with a predicted low or intermediate binding affinity. This demonstrates the importance of including low-affinity binders in the search for epitopes within shared tumor associated antigens (TAAs), as these might be less subject to immune tolerance mechanisms. The study presents four novel TAAs containing multiple possible targets for immunotherapy of breast cancer.

KW - Breast cancer

KW - breast cancer immunogenicity

KW - immunomonitoring

KW - overexpression antigens

KW - shared tumor antigens

KW - TAAs

KW - TAAs in breast cancer

KW - tumor associated antigens

KW - tumor specific CD8+ T cells

KW - tumor specific cytotoxic T cells

U2 - 10.1080/2162402X.2019.1663107

DO - 10.1080/2162402X.2019.1663107

M3 - Journal article

C2 - 31741759

AN - SCOPUS:85073958804

VL - 8

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 12

M1 - 1663107

ER -