Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement.
Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement.
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DOI：
10.1007/s00262-021-02984-7
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
van Hall T
中科院分区：
文献类型：
--
作者：
Marijt KA;Griffioen L;Blijleven L;van der Burg SH;van Hall T
癌细胞经常在其抗原加工途径中显示缺陷，从而逃避CD8 T细胞免疫。我们描述了一种新的癌症抗原，称为TEIPP，它出现在肽泵TAP功能丧失的癌症上。teipp是一种非突变的新抗原，尽管它们的“自我”起源是由于它们在正常组织上的缺失。在这里，我们描述了一种合成的长肽（SLP）疫苗的开发，该疫苗是迄今为止鉴定的最具免疫原性的TEIPP抗原，来源于tap独立的LRPAP1信号序列。lrpap121 - 30特异性CD8 T细胞存在于所有被测试的健康供者以及非小细胞肺腺癌患者的血液中。然而，具有天然侧翼的slp不能被单核细胞来源的树突状细胞交叉呈递。由于LRPAP121-30的c端是一个非常规的弱结合丝氨酸(S)，我们研究了替换这个锚是否会导致有效的交叉呈现。交换成缬氨酸(V)导致更高的HLA-A2结合亲和力和增强的T细胞刺激。重要的是，使用v -变体分离的CD8 T细胞能够将四聚体与天然s -变体结合，并对tap缺陷的癌细胞产生反应。n端和c端延伸slp阵列的功能筛选，指向在n端延长的24-mer V-SLP，作为最理想的候选疫苗。该SLP有效地交叉呈现，并从内源性T细胞库中诱导出强lrpap121 - 30特异性的CD8 T细胞。因此，我们根据LRPAP1信号序列设计了TEIPP SLP疫苗，准备在临床试验中进行验证。在线版本包含补充材料，可在10.1007/s00262-021-02984-7获得。
Cancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials. The online version contains supplementary material available at 10.1007/s00262-021-02984-7.
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影响因子：
7.2
作者：
Doorduijn EM;Sluijter M;Marijt KA;Querido BJ;van der Burg SH;van Hall T
通讯作者：
van Hall T
影响因子：
5.4
作者：
Oliveira, Claudia C.;Querido, Bianca;van Hall, Thorbald
通讯作者：
van Hall, Thorbald
影响因子：
4.4
作者：
Bijker, Martijn S.;van den Eeden, Susan J. F.;van der Burg, Sjoerd H.
通讯作者：
van der Burg, Sjoerd H.
影响因子：
4.8
作者：
Khan, Selina;Bijker, Martijn S.;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry
影响因子：
5.4
作者：
Bijker, Martijn S.;van den Eeden, Susan J. E.;Offringa, Rienk
通讯作者：
Offringa, Rienk