Purpose: Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for “off-the-shelf” adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes. Experimental Design: In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested. Results: Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS. Conclusions: The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for “off-the-shelf” ACTs.

中文翻译：

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鉴定和验证靶向人类癌症中 RAS 热点突变的 T 细胞受体用于基于细胞的免疫治疗

目的：免疫疗法通过触发免疫反应的免疫细胞识别肿瘤抗原来介导人类肿瘤的消退。大约 30% 的癌症患者发生 RAS 癌基因突变。这些突变在肿瘤建立和存活中都起着重要作用，并且常见于热点。因此，发现识别 MHC I 类和 II 类分子上呈现的共享突变 RAS 抗原的 T 细胞受体 (TCR) 是在 TCR 插入淋巴细胞后用于“现成”过继细胞疗法 (ACT) 的有希望的试剂。实验设计：在这项正在进行的工作中，我们筛选了肿瘤浸润淋巴细胞 (TIL) 或体外刺激外周血淋巴细胞 (PBL) 中的 RAS 抗原识别。从反应性 T 细胞中鉴定出识别突变 RAS 的 TCR。然后重建 TCR 并将病毒转导到 PBL 中并进行测试。结果：在这里，我们检测并报告了多个新的 TCR 序列，它们以高亲和力和特异性识别非同义突变 RAS 热点突变，并鉴定了参与识别突变 RAS 的特定 I 类和 -II 类 MHC 限制元件。结论：此处描述的针对 RAS 热点突变的 TCR 文库可识别在约 45% 的高加索人群和约 60% 的亚洲人群中发现的 RAS 突变，并代表了用于“现成”ACTs 的有希望的试剂。我们检测并报告了多个新的 TCR 序列，这些序列以高亲和力和特异性识别非同义突变 RAS 热点突变，并鉴定了参与识别突变 RAS 的特定 I 类和 -II 类 MHC 限制元件。结论：此处描述的针对 RAS 热点突变的 TCR 文库可识别在约 45% 的高加索人群和约 60% 的亚洲人群中发现的 RAS 突变，并代表了用于“现成”ACTs 的有希望的试剂。我们检测并报告了多个新的 TCR 序列，这些序列以高亲和力和特异性识别非同义突变 RAS 热点突变，并鉴定了参与识别突变 RAS 的特定 I 类和 -II 类 MHC 限制元件。结论：此处描述的针对 RAS 热点突变的 TCR 文库可识别在约 45% 的高加索人群和约 60% 的亚洲人群中发现的 RAS 突变，并代表了用于“现成”ACTs 的有希望的试剂。