即使被癌症特异性 T 细胞浸润，癌症最终也会杀死宿主。我们检查了来自荷瘤宿主的 CD4 T 细胞 (CD4TCR) 的癌症特异性 T 细胞受体是否可以用于过继 TCR 治疗。我们专注于针对一种本土突变新抗原的 CD4TCR，该抗原仅由 MHC II 类阴性癌细胞周围的基质呈递。使用 TCR 工程 CD4 T 细胞测试了 11 种最常见的四聚体分选 CD4 TCR。三种 TCR 的特点是聚合重组，其中多个 T 细胞克隆型的核苷酸序列不同，但编码相同的 TCR α 和 β 链。这些优先选择的 TCR 可以同样有效地破坏肿瘤，并通过肿瘤基质的重新编程来阻止肿瘤进展。由单个 T 细胞克隆型代表的 TCR 仅当它们与 α 链和 β 链中优先选择的 TCR 共享 CDR 元件时才同样有效。根据这些特征选择候选 TCR 有助于识别具有潜在治疗效果的 TCR。

Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4+ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.