PDF(Pubmed)
Abstract：
Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.
摘要：
具有足够健康水平的能力T细胞对抗癌症的形成和进展。在多发性骨髓瘤（MM）中，T细胞耗竭是由多种因素引起的，包括肿瘤负荷，由于慢性疾病，持续的免疫激活，年龄,营养状况,和某些MM治疗如烷化剂和蛋白酶体抑制剂。目前使用的许多疗法，包括双特异性T细胞衔接者，抗CD38抗体，蛋白酶体抑制剂，和CART细胞，直接或间接依赖于T细胞的抗癌活性。T细胞适应性的降低不仅降低了免疫防御能力，增加患者对机会性感染的易感性，但会影响MM治疗效果，将可以调节T细胞适应性并可能优化总体获益和临床结局的测序策略纳入焦点。某些用于治疗MM的靶向药物，如核出口(SINE)化合物的选择性抑制剂，有可能减轻T细胞耗尽。本文称为XPO1抑制剂，正弦化合物抑制核出口蛋白1（XPO1），这导致肿瘤抑制蛋白的核保留和激活以及癌蛋白表达的下调。XPO1抑制剂selinexor和eltanexor减少了细胞系和动物模型中的T细胞耗竭，表明它们在活化这些关键效应细胞方面的潜在作用。需要更多的临床研究来了解T细胞适应性如何受到MM疾病和治疗因素的影响。为了潜在地促进现有治疗的最佳使用，和影响，T细胞功能。这篇综述总结了T细胞适应性的重要性以及使用T细胞参与疗法优化治疗的潜力，重点是XPO1抑制剂。
