Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer.
Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer.
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结构提出了一种将弱自肽肿瘤抗原转化为癌症中 CD8 T 细胞超级激动剂的方法
DOI：
10.1073/pnas.2100588118
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发表时间：
2021-06-08
影响因子：
11.1
通讯作者：
Yin L
中科院分区：
文献类型：
--
作者：
Wei P;Jordan KR;Buhrman JD;Lei J;Deng H;Marrack P;Dai S;Kappler JW;Slansky JE;Yin L
使用修饰的自身抗原的肿瘤疫苗在结构上增强了 T 细胞受体-肽-主要组织相容性复合物的相互作用，大大提高了 T 细胞针对肿瘤未修饰的自身抗原的保护反应。这些相互作用的 X 射线晶体结构解释了天然肽和修饰肽如何与相同的 T 细胞受体相互作用，但具有不同的亲和力和驱动 T 细胞增殖和分化的能力。肿瘤经常表达未突变的自身肿瘤相关抗原（自身TAA）。然而，使用自体 TAA 作为癌症疫苗靶点的试验结果好坏参半，这通常归因于 T 细胞在 T 细胞发育过程中删除了具有自体 TAA 高亲和力受体 (TCR) 的 T 细胞。突变这些弱的自身 TAA 以产生更高亲和力的有效疫苗具有挑战性，因为突变可能不会使广泛的自身 TAA 特异性 T 细胞库的所有成员受益。我们之前发现了一种常见的弱鼠自体TAA，我们通过单个氨基酸替换将其转化为高效的抗肿瘤疫苗。在这种情况下，修饰的和天然的自体 TAA 仍然产生非常相似的 CD8 T 细胞组。我们的结构研究表明，自身 TAA 的修饰导致主要组织相容性复合物 I-TAA 结构发生微妙的变化。这种氨基酸取代使得肽在随后的 TCR 结合过程中发生了巨大的构象变化，从而大大增加了 TCR 亲和力，并解释了修饰的自 TAA 作为疫苗的功效。这些结果表明，对免疫原性较差的自身 TAA 进行精心选择、充分表征的修饰可以挽救大量弱反应的天然自身 TAA 特异性 CD8 T 细胞的免疫反应，驱使它们增殖并分化为功能性效应细胞。随后，肿瘤细胞上未经修饰的自 TAA 虽然无法驱动这种反应，但仍然是 CD8 细胞毒性效应器的足够目标。我们的结果提出了一种更有效地识别常见自体 TAA 变体的途径，这可能有助于疫苗开发，补充当前其他非抗原特异性免疫疗法。
Tumor vaccines using modified self-antigens that structurally enhance T cell receptor–peptide–major histocompatibility complex interactions greatly improve a T cell protective response against the tumor’s unmodified self-antigen. X-ray crystal structures of these interactions explain how the native and modified peptides can interact with the same T cell receptor, but with different affinities and abilities to drive T cell proliferation and differentiation. Tumors frequently express unmutated self-tumor–associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA–specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I–TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA–specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies.
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影响因子：
32.4
作者：
Adams JJ;Narayanan S;Liu B;Birnbaum ME;Kruse AC;Bowerman NA;Chen W;Levin AM;Connolly JM;Zhu C;Kranz DM;Garcia KC
通讯作者：
Garcia KC
影响因子：
7.3
作者：
Guo Y;Lei K;Tang L
通讯作者：
Tang L
在肿瘤浸润淋巴细胞上表达的孤儿T细胞受体的抗原鉴定。
影响因子：
64.5
作者：
Gee MH;Han A;Lofgren SM;Beausang JF;Mendoza JL;Birnbaum ME;Bethune MT;Fischer S;Yang X;Gomez-Eerland R;Bingham DB;Sibener LV;Fernandes RA;Velasco A;Baltimore D;Schumacher TN;Khatri P;Quake SR;Davis MM;Garcia KC
通讯作者：
Garcia KC
DOI：
10.1084/jem.176.6.1681
发表时间：
1992-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Corr M;Boyd LF;Frankel SR;Kozlowski S;Padlan EA;Margulies DH
通讯作者：
Margulies DH
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K