TCR Transduced CD4+ T Cells for Adoptive Immunotherapy

在我们最初的研究中，我们首先描述了产生MHC I类限制性CD 4 + T细胞的能力， 用MHC I类限制性TCR基因逆转录病毒转导的正常T细胞。我们随后表明，如果TCR具有足够的亲和力，所得到的MHC 1类限制性CD 4 + T细胞可以识别肿瘤细胞表达的生理水平的抗原。因此，这些新型T细胞可以通过帮助引发肿瘤病变中的宿主免疫应答来增强抗肿瘤免疫应答。它们还可以促进过继转移的CD 8 + T细胞的持久性和功能。 然而，关于TCR转导的CD 4 + T细胞在体内的生物学及其在体外或体内对CD 8 + T细胞的影响还一无所知。我们有初步的数据表明，这种新的群体实际上抑制了CD 8 + T细胞的启动，这与它们的预期功能相反。本研究的目的是更好地了解MHC 1类限制性CD 4 + T细胞在抗肿瘤免疫中的作用。我们的中心假设是，MHC I类限制性TCR转导的CD 4 + T细胞可以通过CD 8 + T细胞增强抗肿瘤免疫应答。我们预测这将通过诱导它们成为能够在体外授权DC引发CD 8 + T细胞的有效Th细胞而发生。我们进一步预测，可以使MHC I类限制性TCR转导的CD 4 + T细胞在体内促进TCR转导的CD 8 + T细胞的存活和功能。这些假设/预测将使用经转导以表达TIL 13831 TCR的小鼠和人CD 4 + T细胞的组合进行测试。将这些识别由HLA-A2呈递的酪氨酸酶：368-376表位的TCR转导的CD 4 + T细胞与它们的正常小鼠或人对应物比较它们分泌细胞因子、许可DC致敏/活化初始和TCR转导的CD 8 + T细胞以及介导体内肿瘤消退的能力。

In our original studies, we first described the ability to generate MHC class I restricted CD4+ T cells by retrovirally transduced normal T cells with MHC class I restricted TCR genes. We subsequently showed that if the TCR had sufficient affinity, the resulting MHC class 1 restricted CD4+ T cells could recognize physiologic levels of antigen expressed by tumor cells. Therefore, these novels T cells could augment the anti-tumor immune response by helping to prime the host immune response in tumor lesions. They could also promote the persistence and function of adoptively transferred CD8+ T cells. However, nothing is known about the biology of TCR transduced CD4+ T cells in vivo and their impact on the CD8+ T cells in vitro or in vivo. We have preliminary data that shows this novel population actually inhibits CD8+ T cell priming which would be contrary to their desired function. The goal of this project is to acquire a better understanding of the role of MHC class 1 restricted CD4+ T cells in anti-tumor immunity. Our central hypothesis is that MHC class I restricted, TCR transduced CD4+ T cells can be made to augment the antitumor immune response by CD8+ T cells. We predict this will occur by inducing them to become potent Th cells capable of licensing DC to prime CD8+ T cells in vitro. We further predict that MHC class I restricted, TCR transduced CD4+ T cells can be made promote the persistence and function of TCR transduced CD8+ T cells in vivo. These hypotheses/predictions will be tested using a combination of mouse and human CD4+ T cells transduced to express the TIL 13831 TCR. These TCR transduced CD4+ T cells, which recognize the tyrosinase: 368-376 epitope presented by HLA-A2, will be compared to their normal mouse or human counterparts for their ability secrete cytokines, license DC to prime/activate naive and TCR transduced CD8+ T cells, and mediate tumor regression in vivo.