Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR , USA.
Front Oncol. 2015 Feb 16;5:34. doi: 10.3389/fonc.2015.00034. eCollection 2015.
Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient's own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as "checkpoint inhibitors," can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the "brakes" on T cells to boost anti-tumor immunity. Generating optimal "killer" CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.
最近的研究强调了免疫疗法的治疗效果，免疫疗法是一类利用患者自身免疫系统来摧毁癌细胞的癌症治疗方法。在肿瘤内，存在一类负调节分子家族，统称为“检查点抑制剂”，它们可以抑制 T 细胞功能，从而抑制抗肿瘤免疫。检查点抑制剂，如 CTLA-4 和 PD-1，会减弱 T 细胞的增殖和细胞因子的产生。用拮抗剂单克隆抗体（mAbs）靶向阻断 CTLA-4 或 PD-1，可以释放 T 细胞的“刹车”，从而增强抗肿瘤免疫。产生最佳的“杀伤”CD8 T 细胞反应还需要 T 细胞受体的激活和共刺激，这可以通过肿瘤坏死因子受体家族成员（包括 OX40（CD134）和 4-1BB（CD137））的配体来提供。OX40 特别引人注目，因为用激活（激动剂）抗-OX40 mAb 治疗可以增强 T 细胞的分化和细胞溶解功能，从而增强对多种肿瘤的抗肿瘤免疫力。当作为单一药物使用时，这些药物可以在转移性疾病患者中引起强烈的临床和免疫反应。然而，这些药物中的每一种都只能使一部分患者受益，这凸显了需要更有效的联合治疗策略的迫切需要。在这篇综述中，我们将讨论我们目前对 OX40 激动剂与检查点抑制剂阻断协同作用增强 T 细胞介导的抗肿瘤免疫的细胞和分子机制的理解，以及联合免疫治疗策略的临床转化的潜在机会。
