4-1BB-Enhanced Expansion of CD8(+) TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8(+) T Cells.
4-1BB-Enhanced Expansion of CD8(+) TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8(+) T Cells.
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DOI：
10.1158/2326-6066.cir-16-0364
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发表时间：
2017-06
影响因子：
10.1
通讯作者：
Reuben JM
中科院分区：
文献类型：
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作者：
Harao M;Forget MA;Roszik J;Gao H;Babiera GV;Krishnamurthy S;Chacon JA;Li S;Mittendorf EA;DeSnyder SM;Rockwood KF;Bernatchez C;Ueno NT;Radvanyi LG;Vence L;Haymaker C;Reuben JM
CD8+肿瘤浸润性淋巴细胞(TIL)高度浸润性三阴性乳腺癌(TNBC)与改善预后有关。这一观察结果使我们假设CD8+TIL可用于TNBC的自体过继细胞治疗，尽管鉴于CD8+TIL在黑色素瘤以外的实体肿瘤中推广的困难，这一概念已被证明具有挑战性。为了克服这一障碍，我们使用了针对TNFR家族成员4-1BB/CD137的激动型抗体(Urelumab)，该抗体由最近激活的CD8+T细胞表达。这种方法首先被用于黑色素瘤，在这项研究中，导致了大多数被测试的TNBC肿瘤TIL的有利生长。该激动型抗体仅在培养初期加入，但仍能促进TNBC肿瘤CD8+TIL的增殖。这些扩增的CD8+TIL具有细胞毒功能，并成功地用于证明在自体TNBC肿瘤组织中存在免疫原性突变，而不识别野生型对应物。我们的发现为成功的TNBC过继免疫疗法开辟了道路。
Triple negative breast cancer (TNBC) highly infiltrated with CD8+ tumor-infiltrating lymphocytes (TILs) 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 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.