Memory potential, molecular characterization, and translational applications of the novel ThEO/TcEO T cell phenotype

黑色素瘤是一种侵袭性皮肤癌，占皮肤癌相关死亡的大部分。 然而，新开发的治疗方法为治疗这种曾经无法治愈的疾病带来了希望。 免疫治疗的进展，特别是批准抗CTLA-4和抗PD-1治疗黑色素瘤和 非小细胞肺癌不仅在治疗方面显示出免疫调节的潜力，而且 治疗转移癌。这些检查点阻断抗体的临床成功扩大了 靶向其他T细胞共受体靶点增强强大的抗肿瘤免疫反应的可能性 可能会带来更大的临床益处。针对共刺激受体4-1BB的激动剂抗体的使用 在活化的T细胞上表达，已被证明对两种系统中的多种肿瘤类型都有效 以及早期的人体临床试验。α4-1BB疗法在增强抗肿瘤免疫方面的精妙效力是 部分原因是由于4-1BB介导的T细胞编程呈现由T细胞驱动的高度细胞毒表型 框转录因子Eomesodermin(EOMES)与共抑制受体的表达 KLRG1.这些Eome+KLRG1+CD8(TCEO)和CD4(Theo)T细胞介导了强大的抗肿瘤反应 能够完全排斥肿瘤。我们假设这个由Eome驱动的Theo/TCEO T细胞 表型代表了一种新的分子程序，它形成稳定的免疫记忆，尽管 维持高细胞毒效应功能和KLRG1的表达。通过描述独特的 4-1BB激活的下游通路创建了Theo程序，我们将建立分子 这些细胞具有极强的细胞毒性以及它们打破范式表达能力的基础 KLRG1仍保持增殖能力和记忆潜能。详细记忆表型的研究 这些细胞，以及它们在抗原重新挑战后的复制能力和寿命将加深我们的 了解4-1BB激动剂抗体的免疫生物学，并深入了解它们在 细胞治疗环境。最后，探讨Theo表型T细胞在调节两者之间的重要性。 与4-1BB激动剂相关的有益的抗肿瘤疗效和有害的肝脏炎症 抗体将为未来的临床研究提供机械性的见解和潜在的指导性生物标志物。这个 拟议的研究项目将提供广泛的基础和临床研究、科学研究方面的技术培训 写作、协作和实验室管理是作为一名独立调查员追求职业生涯所必需的。

Melanoma is an aggressive form of skin cancer that accounts for the majority of skin cancer related deaths. Newly developed therapeutic modalities, however, have offered hope in treating this once incurable disease. Advances in immunotherapy, particularly the approval of anti-CTLA-4 and anti-PD-1 therapy for melanoma and non-small-cell lung cancer have demonstrated the potential of immune modulation in not only treating, but curing metastatic cancers. The clinical success of these checkpoint blockade antibodies has expanded the potential of targeting other T cell co-receptor targets to potentiate robust anti-tumor immune responses that may afford greater clinical benefit. Use of agonist antibodies directed towards 4-1BB, a co-stimulatory receptor expressed on activated T cells, has proven effective in treating multiple tumor types in both murine systems and early human clinical trials. The exquisite potency of α4-1BB therapy in boosting anti-tumor immunity is due, in part, to 4-1BB-mediated programming of T cells to assume a highly cytotoxic phenotype driven by the T box transcription factor Eomesodermin (Eomes) and characterized by expression of the co-inhibitory receptor KLRG1. These Eomes+KLRG1+ CD8 (TcEO) and CD4 (ThEO) T cells mediate potent anti-tumor responses capable of complete tumor rejection. We hypothesize that this Eomes-driven ThEO/TcEO T cell phenotype represents a novel molecular program which forms stable immunologic memory despite maintenance of highly cytotoxic effector function and KLRG1 expression. By characterizing the unique pathways downstream of 4-1BB activation which create the ThEO program, we will establish the molecular basis for the exquisite cytotoxicity of these cells, as well as their paradigm-breaking capacity to express KLRG1 yet retain proliferative capacity and memory potential. Investigating the detailed memory phenotype of these cells, as well as their replicative capacity and longevity following antigenic rechallenge will deepen our understanding of 4-1BB agonist antibody immunobiology and provide insight into their translational value in a cell therapy setting. Finally, exploring the importance of ThEO phenotype T cells for mediating both the beneficial anti-tumor efficacy as well as the detrimental liver inflammation associated with 4-1BB agonist antibody will provide mechanistic insights as well as potential guiding biomarkers for future clinical studies. The proposed research project will provide extensive technical training in both basic and clinical research, scientific writing, collaboration, and lab management necessary to pursue a career as an independent investigator.