4-1BB-Enhanced Expansion of CD8 + TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8 + T Cells

Triple-negative breast cancer (TNBC) highly infiltrated with CD8 tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8 TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to b...

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Bibliographic Details
Published in:Cancer immunology research 2017-06, Vol.5 (6), p.439-445
Main Authors: Harao, Michiko, Forget, Marie-Andrée, Roszik, Jason, Gao, Hui, Babiera, Gildy V, Krishnamurthy, Savitri, Chacon, Jessica A, Li, Shumin, Mittendorf, Elizabeth A, DeSnyder, Sarah M, Rockwood, Korrene F, Bernatchez, Chantale, Ueno, Naoto T, Radvanyi, Laszlo G, Vence, Luis, Haymaker, Cara, Reuben, James M
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - pharmacology
CD8-Positive T-Lymphocytes - immunology
Female
Humans
Lymphocytes, Tumor-Infiltrating - immunology
Mutation
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - immunology
Tumor Cells, Cultured
Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology
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Summary:Triple-negative breast cancer (TNBC) highly infiltrated with CD8 tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8 TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8 TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8 T cells. This approach was first utilized in melanoma and, in this study, led to advantageous growth of TILs for the majority of TNBC tumors tested. The agonistic antibody was only added in the initial setting of the culture and yet favored the propagation of CD8 TILs from TNBC tumors. These expanded CD8 TILs were capable of cytotoxic functions and were successfully utilized to demonstrate the presence of immunogenic mutations in autologous TNBC tumor tissue without recognition of the wild-type counterpart. Our findings open the way for a successful adoptive immunotherapy for TNBC. .
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-16-0364