Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy.
Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy.
复制标题
将 IL-2 信号转导重新靶向表达 NKG2D 的肿瘤浸润白细胞可改善过继转移免疫疗法。
DOI：
10.4049/jimmunol.2000926
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Krupnick AS
中科院分区：
文献类型：
--
作者：
Banerjee A;Li D;Guo Y;Mahgoub B;Paragas L;Slobin J;Mei Z;Manafi A;Hata A;Li K;Shi L;Westwick J;Slingluff C;Lazear E;Krupnick AS
Ex vivo expansion followed by reinfusion of tumor infiltrating leucocytes (TILs) has been utilized successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine interleukin-2 (IL-2) to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 post-reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic due to its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. Here we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high affinity IL-2 receptor for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident cytotoxic lymphocytes, such as CD8+ T cells, NK cells, and γδT cells while wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2 expanded cytotoxic lymphocytes express higher levels of tumor homing receptors such as LFA-1, CD49a and CXCR3 which correlate with TIL localization to the tumor bed after intravenous injection. Consistent with this OMCPmutIL-2 expanded TILs provided superior tumor control compared to those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D expressing cytotoxic lymphocytes rather than indiscriminate expansion of all TILs.
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影响因子：
8.8
作者：
Baldan, V.;Griffiths, R.;Hawkins, R. E.;Gilham, D. E.
通讯作者：
Gilham, D. E.
影响因子：
7.3
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通讯作者：
Davis DM
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3.9
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Rosenberg, SA
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通讯作者：
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