Targeting PIM-2 Kinase for Improving Cancer Immunotherapy

摘要 适应性免疫系统具有识别和杀死恶性细胞的能力。免疫耐受 正常情况下保护健康组织免受自身免疫攻击的机制可以防止 有效的抗肿瘤免疫。肿瘤使用许多免疫抑制机制来逃避 有效的T细胞反应。越来越多的免疫逃避机制已被表征 包括分子和细胞机制。尽管针对一个或多个国家取得了可喜的成果， 这些免疫逃避机制，显然有改进的空间，因为只有一个子集的癌症 患者通常对这种治疗有反应。PIM激酶在肿瘤发生中已被广泛研究 并作为各种癌症的潜在治疗靶点。PIM激酶也在活化的T细胞上表达， 但它们在T细胞活性和功能中的作用尚不确定， 仍然不清楚。使用基因突变小鼠，我们发现单个PIM激酶发挥独特的作用， 在T细胞对同种异体抗原应答中的重叠作用。令人惊讶的是，我们一直观察到PIM-2缺陷型T细胞 细胞诱导移植物抗宿主病（GVHD）的能力显著增加， 骨髓移植（BMT）。更重要的是，我们发现，CD 8 T细胞能够显著增强抗- 当PIM-2缺陷或被阻断时，肿瘤反应。我们的初步研究已经从 从遗传学到药理学方法，从小鼠到人类T细胞。因此，我们的初步研究提供了 令人信服的证据表明，PIM-2作为一个强大的负调节T细胞免疫抗癌。我们 中心假设是靶向PIM-2实质上促进癌症免疫治疗，同时潜在地 直接抑制肿瘤进展。这一假设将在以下两个具体目标中得到检验：1） 描述PIM-2负调节T细胞应答的机制作用; 2）验证PIM-2作为T细胞应答的抑制剂， 针对癌症免疫疗法。根据我们令人信服的初步数据， 当PIM-2负调节T细胞免疫时，我们希望坚定地验证这一观察结果，并确定 这种调节发生的细胞和分子机制。我们还希望证明， 阻断或抑制PIM-2将增强针对不同类型癌症的抗肿瘤免疫， 小鼠和人类T细胞。

Abstract The adaptive immune system has the capacity to recognize and kill malignant cells. However, immune tolerant mechanisms that normally protect healthy tissues from autoimmune attack prevent the development of effective anti-tumor immunity. Tumor uses numerous immunosuppressive mechanisms to evade otherwise effective T-cell responses. A growing number of immune evasion mechanisms have been characterized including molecular and cellular mechanisms. Despite promising results achieved by targeting one or more of these immune evasion mechanisms, there is clearly room for improvement since only a subset of cancer patients usually respond to such a treatment. The PIM kinases have been studied extensively in tumorigenesis and as potential therapeutic targets for various cancers. PIM kinases are also expressed on activated T cells, but their roles in T-cell activity and function are inconclusive and the functions of each isoform in these cells remain unclear. Using genetically mutant mice, we found that individual PIM kinases play unique as well as overlapping roles in T-cell response to alloantigens. Strikingly, we consistently observed that PIM-2-deficient T cells had significantly increased ability to induce graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). More importantly, we found that CD8 T cells mount substantially strong anti- tumor responses when PIM-2 was deficient or blocked. Our preliminary studies have been extended from genetic to pharmacologic approaches and from mouse to human T cells. Thus, our preliminary studies provide compelling evidence that PIM-2 serves as a powerful negative regulator of T-cell immunity against cancer. Our Central Hypothesis is that targeting PIM-2 substantially promotes cancer immunotherapy while potentially inhibiting tumor progression directly. This hypothesis will be tested in the following two Specific Aims: 1) To delineate mechanistic action by which PIM-2 negatively regulates T-cell response; 2) To validate PIM-2 as an immunotherapy target against cancer. Based on our compelling preliminary data demonstrating for the first time that PIM-2 negatively regulates T-cell immunity, we expect to firmly validate this observation and to define the cellular and molecular mechanisms by which this regulation occurs. We also expect to demonstrate that blockade or inhibition of PIM-2 will enhance anti-tumor immunity against different types of cancer mediated by both mouse and human T cells.