Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors.
Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors.
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DOI：
10.1080/2162402x.2021.1936757
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发表时间：
2021
期刊：
影响因子：
7.2
通讯作者：
Inderberg EM
中科院分区：
文献类型：
--
作者：
Dillard P;Casey N;Pollmann S;Vernhoff P;Gaudernack G;Kvalheim G;Wälchli S;Inderberg EM
T细胞受体（TCR）重定向的T细胞被认为是治疗许多实体瘤的下一代护理。KRAS突变是在超过25%的所有癌症中表达的驱动新抗原，因此被认为是免疫细胞疗法（ACT）的理想靶标。我们已经从用突变的KRAS肽的混合物接种的长期存活的胰腺癌患者中分离出四种KRAS特异性TCR。这些TCR的序列可以在原代细胞中鉴定和表达。当表达T细胞与呈递KRAS肽的靶细胞共孵育时，我们证明了所有TCR的稳定表达以及靶特异性功能。此外，这些TCR都是部分共受体非依赖性的，因为它们在CD4和CD8 T细胞中都有功能，因此表明高亲和力。有趣的是，我们观察到某些TCR能够识别与其同源人类白细胞抗原（HLA）复合的几个KRAS突变，这表明，在这里，点突变对于HLA结合和TCR识别不太重要，而其他点突变是单突变限制的。最后，我们证明了这些肽确实被加工和呈递，因为外源负载KRAS蛋白的HLA匹配的抗原呈递细胞被TCR转导的T细胞识别。总之，我们的数据表明，KRAS突变对CD4 T细胞具有免疫原性，并且是基于TCR的癌症免疫治疗的有趣靶点。
T-cell receptor (TCR) redirected T cells are considered as the next generation of care for the treatment of numerous solid tumors. KRAS mutations are driver neoantigens that are expressed in over 25% of all cancers and are thus regarded as ideal targets for Adoptive Cell Therapy (ACT). We have isolated four KRAS-specific TCRs from a long-term surviving pancreatic cancer patient vaccinated with a mix of mutated KRAS peptides. The sequence of these TCRs could be identified and expressed in primary cells. We demonstrated stable expression of all TCRs as well as target-specific functionality when expressing T cells were co-incubated with target cells presenting KRAS peptides. In addition, these TCRs were all partially co-receptor independent since they were functional in both CD4 and CD8 T cells, thus indicating high affinity. Interestingly, we observed that certain TCRs were able to recognize several KRAS mutations in complex with their cognate Human leukocyte antigen (HLA), suggesting that, here, the point mutations were less important for the HLA binding and TCR recognition, whereas others were single-mutation restricted. Finally, we demonstrated that these peptides were indeed processed and presented, since HLA-matched antigen presenting cells exogenously loaded with KRAS proteins were recognized by TCR-transduced T cells. Taken together, our data demonstrate that KRAS mutations are immunogenic for CD4 T cells and are interesting targets for TCR-based cancer immunotherapy.